Diastereoselective synthesis method and application of polysubstituted cyclobutane

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a diastereoselective synthesis method and application of polysubstituted cyclobutane. The preparation method comprises the following steps: adding 3-methylene cyclobutyl tertiary alcohol, alkyl halide (or acyl and sulfonyl halide) and a photocatalyst into an organic solvent, and reacting in a nitrogen atmosphere and under the irradiation of a blue light LED lamp to generate cis-1, 3-bifunctional cyclobutane with a single configuration. The photocatalyst used in the method does not contain metal and is small in dosage, wide in substrate range and high in stereoselectivity. In addition, according to the invention, the product is successfully subjected to a one-step cyclization reaction under the action of alkali to generate polysubstituted bicyclo [2.1. 1] hexane. According to the application, heteroaryl with various structures is successfully introduced to bridgehead carbon of bicyclo [2.1. 1] hexane, and functional groups such as cyano groups and aldehyde groups which are easy to modify and convert as well as bromine atoms and fluorine atoms which are difficult to introduce in a traditional method are also introduced. The synthesis method has the advantages of high efficiency, simplicity, wide substrate universality, good functional group compatibility and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for diastereoselective synthesis of polysubstituted cyclobutanes and its application. Background Art

[0002] Cyclobutanes and bicyclo[2.1.1]hexanes (BCHs), as a class of saturated carbocyclic compounds with three-dimensional configurations, are rich in sp³ hybridized carbons, have rigid conformations and good metabolic stability. These properties make them ideal bioisosteres of benzene rings. In addition, 1,3-difunctionalized cyclobutanes can also serve as rigid alternative skeletons for ethyl and propyl groups, thereby restricting the conformation of drug molecules. Bioactive molecules incorporating this structure can improve the metabolic stability of drug molecules, enhance the binding force between drugs and targets, and increase the bioavailability of drugs, etc. (see ChemMedChem. 2022, 17, e202200020.), opening up new ideas for new drug research and development.

[0003] In the field of organic chemistry, the synthesis of 1,3-difunctionalized cyclobutanes is of great importance. Its diastereoselective synthesis has always been a research hotspot and difficulty in the chemical field. Currently, the construction methods mainly include photocatalytic intermolecular [2+2] cycloaddition (see Chem. Rev. 2016, 116, 9748−9815.), [3+1] cycloaddition reaction (see Chem. Sci. 2023,14, 963), the ring-opening reaction of bicyclo[1.1.0]butane with the release of ring strain as the driving force of the reaction, and then reacting with polar nucleophiles or free radicals to generate polysubstituted cyclobutane products (see Commun Chem. 2023, 6, 9.), as well as the regioselective C-H bond chlorination reaction of cyclobutane itself (Angew. Chem. Int. Ed. 2018, 57, 1251-1255.). However, these strategies generally have the problem of difficult to control the cis- and trans-selectivity of the reaction, and most of them rely on special and difficult-to-obtain reaction substrates, such as activated alkenes, 1,1-diborylalkanes, bicyclo[1.1.0]butane, etc. Therefore, it is of great significance to develop new synthesis methods to achieve the diastereoselective synthesis of 1,3-difunctionalized cyclobutanes.

[0004] Currently, the synthesis of BCHs mainly relies on the cycloaddition reaction of bicyclo[1.1.0]butane (BCB) (see Nat. Rev Chem. 2024, 8, 605 - 627.). However, limited by the availability of raw materials, the connection of bicyclo[1.1.0]butane needs to carry an electron-withdrawing group or an aromatic substituent for the reaction to proceed efficiently, and it has poor tolerance to alkyl substituents, resulting in poor functional group compatibility of the products. At the same time, most radical reactions rely on electron-deficient alkenes, and electron-rich alkenes are difficult to participate, greatly limiting the generality of substrates. Some methods also have poor tolerance to substrates containing functional groups such as halogens and cyano groups. Currently, on the bridgehead carbon of bicyclo[2.1.1]hexane, the substituents are mainly limited to aryl groups, and alkyl groups are only commonly methyl groups. Introducing functional groups that can be modified and transformed on the bridgehead carbon faces many challenges, seriously hindering the diversity of the synthesis of bicyclo[2.1.1]hexane (BCHs) and the application expansion in related fields. Therefore, there is an urgent need to develop new synthetic strategies to construct structurally diverse BCHs and promote the development of related fields. Summary of the Invention

[0005] To solve the problems of reaction selectivity, substrate applicability, and functional group compatibility in the existing synthesis methods of cyclobutane and bicyclo[2.1.1]hexane, the purpose of the present invention is to provide a method for the diastereoselective synthesis of polysubstituted cyclobutane, and another purpose of the present invention is to provide an application of the above polysubstituted cyclobutane compound.

[0006] The present invention adopts a strategy of intramolecular distal functional group transannular migration involving free radicals. Under the irradiation of a blue LED lamp, after the photocatalyst absorbs the blue light energy of a specific wavelength, it is excited to a high-energy state. The photocatalyst in the high-energy state transfers the energy to the halide, and through single-electron transfer, the carbon-halogen bond in the halide molecule undergoes homolytic cleavage to generate free radicals. The generated free radicals have high reactivity and will attack the methylene double bond of 3-methylenecyclobutyl tert-alcohol to form a new active alkyl radical. This radical is quickly captured by the distal migrating group to generate a bicyclo[2.1.1]hexane transition state. Subsequently, the C-C bond breaks, and the migrating group undergoes transannular migration to highly stereoselectively generate cis-1,3-bifunctionalized cyclobutane. The cis-1,3-bifunctionalized cyclobutane undergoes an intramolecular nucleophilic substitution reaction under the action of a base to form bicyclo[2.1.1]hexane.

[0007] A cis-1,3-bifunctionalized cyclobutane compound with a single configuration according to the present invention has a structural general formula as shown in formula (I):

[0008] Formula (I)

[0009] Wherein: R 1Selected from phenyl, substituted phenyl or cyclohexyl, wherein the substituent on the benzene ring of the substituted phenyl is C1-C4 alkyl, C1-C4 alkoxy or halogen; R 2 is C1-C8 alkyl, fluoroalkyl, acyl, sulfonyl; FG is thiazole, benzothiazole, thiophene, benzofuran, oxime group, cyano group, aldehyde group.

[0010] The synthesis method of a single-configuration cis-1,3-bifunctionalized cyclobutane compound according to the present invention is characterized by comprising the following steps: adding 3-methylenecyclobutyl tertiary alcohol, any one of alkyl halides, acyl halides and sulfonyl halides, and a photocatalyst into an organic solvent, reacting under a nitrogen atmosphere and irradiation of a blue LED lamp, and stirring at room temperature for 8-24 hours to generate a single-configuration cis-1,3-bifunctionalized cyclobutane. The reaction process is shown in the following formula (II):

[0011] Formula (II)

[0012] Wherein: R 1 Selected from phenyl, substituted phenyl or cyclohexyl, wherein the substituent on the benzene ring of the substituted phenyl is C1-C4 alkyl, C1-C4 alkoxy or halogen; R 2 is C1-C8 alkyl, fluoroalkyl, acyl, sulfonyl; FG is thiazole, benzothiazole, thiophene, benzofuran, oxime group, cyano group, aldehyde group.

[0013] Further, in the above technical solution, when the halogenated reagent is an alkyl halide, the molar ratio of 3-methylenecyclobutyl tertiary alcohol, alkyl halide to photocatalyst is 1:1.2-1.5:0-0.02, preferably 1:1.5:0.005; when the halogenated reagent is an acyl halide, the molar ratio is 1:2:0.01-0.02, preferably 1:2:0.02; when the halogenated reagent is a sulfonyl halide, the molar ratio is 1:2:0.0005-0.01, preferably 1:2:0.0005.

[0014] Further, in the above technical solution, the reaction is carried out in an organic solvent, and the organic solvent is selected from one of acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, chlorobenzene, 1,4-dioxane, N,N-dimethylformamide, preferably acetonitrile.

[0015] Further, in the above technical solution, the dosage of the solvent for the reaction is preferably 80 mL / mmol.

[0016] Further, in the above technical solution, the reaction requires a blue LED lamp with a wavelength of 450-460 nm.

[0017] Further, in the above technical solution, the organic photocatalyst is 4-CzIPN, Ir(dtbbpy)(ppy) 2 PF 6 , f ac-Ir(ppy) 3 , rhodamine B, rose bengal. Preferably 4-CzIPN.

[0018]

[0019] Further, in the above technical solution, the reaction is carried out in an anhydrous and anaerobic environment under nitrogen protection and stirred at room temperature for 8 - 24 hours.

[0020] The poly-substituted bicyclo[2.1.1]hexane compound of the present invention has the structural general formula shown in formula (III):

[0021] Formula (III)

[0022] Wherein: FG is thiazole, benzothiazole, thiophene, benzofuran, oxime group, cyano group, aldehyde group; Ar is selected from phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is p-methoxy; X is selected from fluorine atom or bromine atom.

[0023] The synthesis method of a poly-substituted bicyclo[2.1.1]hexane of the present invention is characterized by comprising the following steps: using the obtained cis-1,3-bifunctionalized cyclobutane as the starting material, adding the starting material into a dry reaction tube filled with a nitrogen atmosphere at room temperature, adding tetrahydrofuran as the reaction solvent to form a reaction system; cooling the reaction system to 0 °C in an ice-water bath. Under a nitrogen atmosphere, add a base to the reaction system dropwise at an average rate of one drop every 3 seconds. Then slowly return to room temperature and continue stirring. Monitor the reaction by TLC until the reaction is complete. After the reaction is completed, add a saturated NH 4 Cl aqueous solution to quench the reaction, add an organic solvent ethyl acetate for extraction and layering; take the organic layer, dry it over anhydrous sodium sulfate, filter, concentrate to obtain a crude product, and separate the crude product by column chromatography to obtain the target product poly-substituted bicyclo[2.1.1]hexane. The reaction process is shown in the following formula (IV):

[0024] Formula (IV)

[0025] Wherein: FG is thiazole, benzothiazole, thiophene, benzofuran, oxime group, cyano group, aldehyde group; Ar is selected from phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is p-methoxy; X is selected from fluorine atom or bromine atom.

[0026] Further, in the above technical solution, the molar ratio of the starting material cis-1,3-bifunctionalized cyclobutane to the added base is 1:1.05 - 1.2. The added base is selected from potassium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide. When X is a bromine atom, potassium bis(trimethylsilyl)amide is preferred; when X is a fluorine atom, lithium bis(trimethylsilyl)amide is preferred.

[0027] Further, in the above technical solution, the reaction temperature is first stirred at 0 °C for 0.5 hours, and then slowly restored to room temperature and stirred for 1 - 2 hours until the reaction is completed.

[0028] Further, in the above technical solution, the reaction is carried out in a nitrogen-protected anhydrous and anaerobic environment using tetrahydrofuran as the reaction solvent.

[0029] Further, in the above technical solution, after the reaction, column chromatography is carried out with a mixed solvent of petroleum ether and ethyl acetate, and the eluent ratio of petroleum ether and ethyl acetate is adjusted in a timely manner according to the separation effect.

[0030] Compared with the prior art, the method for the diastereoselective synthesis and application of a polysubstituted cyclobutane according to the present invention has the following advantages and beneficial effects:

[0031] (1) The method of the present invention successfully realizes the construction of highly stereoselective 1,3-bifunctionalized cyclobutane through a radical-involved intramolecular distal functional group transannular migration strategy. This innovative synthesis method opens up a new path for the diastereoselective synthesis of polysubstituted cyclobutanes and enriches the synthetic methodology of cyclobutane compounds. Compared with traditional synthesis methods, the method of the present invention uses cheap and easily available raw materials and reagents, reducing production costs; the photocatalyst is metal-free and has a small dosage, reducing the impact on the environment and also reducing the cost of the catalyst; the substrate scope is wide, capable of accommodating substrates with different structures; it has high stereoselectivity and can accurately obtain the target product with a single configuration; the operation is simple, stable and efficient, and a high yield can be obtained under relatively mild conditions.

[0032] (2) The synthesis method of the present invention successfully solves the problem of introducing structurally diverse heteroaryl groups at the bridgehead carbon of bicyclo[2.1.1]hexane. This method can not only smoothly introduce functional groups such as cyano and aldehyde groups that are easy to modify and transform, but also successfully introduce bromine atoms and fluorine atoms that are difficult to introduce in traditional methods. This application greatly enriches the substrate scope of bicyclo[2.1.1]hexane, shows good functional group compatibility, and opens up a new and effective way for the synthesis of bicyclo[2.1.1]hexane. Specific Embodiments

[0033] The above content of the present invention will be further described in detail through the following examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology implemented based on the above content of the present invention belongs to the scope of the present invention.

[0034] Example 1

[0035] The preparation of cis-1,3-bifunctionalized cyclobutane 3a, and the reaction equation is as follows:

[0036] At room temperature, 3-methylenecyclobutanol 1a (61.4 mg, 0.2 mmol), ethyl difluorobromoacetate 2a (60.9 mg, 0.3 mmol) were successively added to a dry 25 mL Schlenk reaction tube filled with a nitrogen atmosphere. 19.73 mg of the organic photocatalyst 4-CzIPN was dissolved in 50 mL of acetonitrile, and 2 mL (0.789 mg, 0.001 mmol, 0.005 eq.) was withdrawn and added to the reaction tube, and then 14 mL of dry acetonitrile was added. After sealing the reaction tube, it was placed under a 35 W blue LED lamp for irradiation and stirred for 10 hours. After the reaction was completed, the reaction solvent was removed using a rotary evaporator to obtain a crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow oil 3a (78 mg, 91%).

[0037] The NMR data of 3a is as follows:

[0038] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 – 7.87 (m, 3H), 7.84 (d, J = 8.0 Hz,1H), 7.61 – 7.54(m, 1H), 7.51 – 7.40 (m, 3H), 7.38 – 7.31 (m, 1H), 4.16 (p, J = 8.8 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.24 – 3.04 (m, 4H), 2.95 – 2.84 (m,2H), 1.15 (t, J = 7.2 Hz, 3H).

[0039] 13 C NMR (101 MHz, CDCl 3 ) δ 199.2, 176.8, 163.6 (J = t, 40.4 Hz), 153.1, 135.3, 135.1, 133.4, 128.8, 128.4, 126.1, 125.0, 122.8, 121.7, 115.6( J = t, 252.5 Hz), 63.0, 43.4 ( J = t, 30.3 Hz), 40.2 ( J = t, 3.3 Hz), 36.8, 36.0, 13.7.

[0040] 19 F NMR (376 MHz, CDCl 3 ) δ -100.92 (m).

[0041] Example 2

[0042] Preparation of cis-1,3-bifunctionalized cyclobutane 3b, the reaction equation is as follows:

[0043] The operation is the same as in Example 1 of the present invention. The amounts of reactants used are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), tribromomethane 2b (75.8 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (2 mL, 0.789 mg, 0.001 mmol), acetonitrile 14 mL, and stirred for 10 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow oil 3b (91.6 mg, 96%).

[0044] The NMR data of 3b are as follows:

[0045] 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (m, 1H), 7.91 – 7.85 (m, 3H), 7.61 – 7.54 (m, 1H), 7.47 (m, 3H), 7.38 (m, 1H), 5.69 (t, J = 6.8 Hz, 1H), 4.14 (p, J = 8.8 Hz, 1H), 3.46 (d, J = 6.8Hz, 2H), 3.13 – 3.05 (m, 2H), 3.04 – 2.96 (m, 2H).

[0046] 13 C NMR (101 MHz, CDCl 3 ) δ 199.2, 175.9, 153.2, 135.0, 135.0, 133.4, 128.8, 128.4, 126.3, 125.2, 123.0, 121.8, 54.2, 44.3, 40.8, 37.0, 36.4.

[0047] Example 3

[0048] Preparation of cis-1,3-bifunctionalized cyclobutane 3c, the reaction equation is as follows:

[0049] The operation is the same as in Example 1 of the present invention. The amounts of reactants used are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), ethyl bromoacetate 2c (50.1 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (2 mL, 0.789 mg, 0.001 mmol), acetonitrile 14 mL, and stirred for 24 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow oil 3c (71 mg, 90%).

[0050] The NMR data of 3c are as follows:

[0051] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (m, 1H), 7.90 (m, 2H), 7.83 (m, 1H), 7.55 (m, 1H), 7.49 – 7.39 (m, 3H), 7.33 (m, 1H), 4.18 – 4.04 (m, 3H), 3.13 – 2.99 (m, 2H), 2.68 – 2.48 (m, 4H), 2.36 – 2.27 (m, 2H), 1.21 (t, J J = 7.2 Hz, 3H).

[0052] 13 C NMR (101 MHz, CDCl 3) δ 199.6, 177.4, 173.2, 153.1, 135.3, 135.2, 133.2, 128.7, 128.4, 126.0, 124.9, 122.9, 121.7, 60.6, 42.7, 36.5, 35.69, 35.65, 30.1, 14.2.

[0053] Example 4

[0054] Preparation of cis-1,3-bifunctionalized cyclobutane 4a, the reaction equation is as follows:

[0055] At room temperature, 3-methylenecyclobutanol 1a (61.4 mg, 0.2 mmol), organic photocatalyst 4-CzIPN (3.2 mg, 0.004 mmol), benzoyl chloride 2d (56.2 mg, 0.4 mmol), and acetonitrile 16 mL were successively added to a dry 25 mL Schlenk reaction tube filled with a nitrogen atmosphere. After the reaction tube was sealed, it was placed under two 35 W blue LED lights for irradiation and stirred for 24 hours. After the reaction was completed, the reaction solvent was removed using a rotary evaporator to obtain a crude product, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow solid 4a (58.5 mg, 71%).

[0056] The NMR data of 4a are as follows:

[0057] 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 – 7.95 (m, 2H), 7.94 – 7.88 (m, 2H), 7.85 – 7.77 (m, 2H), 7.58 – 7.50 (m, 2H), 7.48 – 7.40 (m, 4H), 7.39 – 7.33 (m, 1H), 7.31 – 7.24 (m, 1H), 4.18 – 4.10 (m, 1H), 4.09 (s, 2H), 3.20 – 3.11 (m, 2H), 2.90 – 2.80 (m, 2H).

[0058] 13 C NMR (101 MHz, CDCl 3) δ 199.5, 197.3, 178.5, 153.4, 137.0, 135.3,135.3, 133.3, 128.8, 128.6, 128.4, 128.1, 125.8, 124.6, 122.7, 121.6, 47.6,41.1, 36.9, 36.4.

[0059] Example 5

[0060] Preparation of cis-1,3-difunctionalized cyclobutane 4b, the reaction equation is as follows:

[0061] The operation is the same as in Example 4 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), organic photocatalyst 4-CzIPN (3.2 mg, 0.004 mmol), p-methoxybenzoyl chloride 2e (68.2 mg, 0.4 mmol), acetonitrile 16 mL, and stirred for 24 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain 4b as a yellow foam (70.2 mg, 80%).

[0062] The NMR data of 4b are as follows:

[0063] 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 – 7.88 (m, 4H), 7.86 – 7.76 (m, 2H),7.58 – 7.51 (m, 1H), 7.50 – 7.41 (m, 2H), 7.41 – 7.33 (m, 1H), 7.31 – 7.25(m, 1H), 6.90 (m, 2H), 4.19 – 4.06 (m, 1H), 4.03 (s, 2H), 3.84 (s, 3H), 3.19– 3.08 (m, 2H), 2.91 – 2.80 (m, 2H).

[0064] 13 C NMR (101 MHz, CDCl 3 ) δ 199.6, 195.8, 178.7, 163.6, 153.4, 135.3, 135.3, 133.3, 130.4, 130.1, 128.7, 128.4, 125.8, 124.5, 122.7, 121.6, 113.8, 55.5, 47.3, 41.2, 36.9, 36.5.

[0065] Example 6

[0066] Preparation of cis-1,3-bifunctionalized cyclobutane 4c, the reaction equation is as follows:

[0067] The operation is the same as that in Example 4 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), organic photocatalyst 4-CzIPN (3.2 mg, 0.004 mmol), m-bromobenzoyl chloride 2f (87.8 mg, 0.4 mmol), acetonitrile 16 mL, and stirred for 24 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain 4c as a yellow foam (73.4 mg, 75%).

[0068] The NMR data of 4c are as follows:

[0069] 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 – 8.08 (m, 1H), 7.96 – 7.86 (m, 3H), 7.85 – 7.77 (m, 2H), 7.66 (m, 1H), 7.56 (m, 1H), 7.46 (m, 2H), 7.42 – 7.34 (m, 1H), 7.34 – 7.24 (m, 2H), 4.20 – 4.09 (m, 1H), 4.05 (s, 2H), 3.20 – 3.09 (m, 2H), 2.91 – 2.79 (m, 2H).

[0070] 13 C NMR (101 MHz, CDCl 3 ) δ 199.4, 196.1, 178.1, 153.3, 138.7, 136.1, 135.3, 135.2, 133.4, 131.3, 130.2, 128.8, 128.4, 126.6, 125.9, 124.7, 123.0, 122.7, 121.7, 47.5, 41.2, 36.9, 36.3.

[0071] Example 7

[0072] Preparation of cis-1,3-difunctionalized cyclobutane 5a, the reaction equation is as follows:

[0073] The operation is the same as in Example 1 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), benzenesulfonyl chloride 2g (53.0 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (0.2 mL, 0.0789 mg, 0.0001 mmol), acetonitrile 15.8 mL, stirred for 12 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow solid 5a (73.3 mg, 82%).

[0074] The NMR data of 5a are as follows:

[0075] 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 – 7.89 (m, 2H), 7.75 (m, 1H), 7.69 – 7.61 (m, 3H), 7.61 – 7.56 (m, 1H), 7.53 – 7.46 (m, 2H), 7.41 – 7.35 (m, 1H), 7.34 – 7.29 (m, 1H), 7.25 – 7.19 (m, 1H), 7.18 – 7.11 (m, 2H), 4.32 – 4.20 (m, 3H), 3.22 – 3.14 (m, 2H), 3.11 – 3.03 (m, 2H).

[0076] 13 C NMR (101 MHz, CDCl 3 ) δ 198.9, 174.9, 153.0, 139.9, 135.1, 134.9, 133.5, 133.1, 128.8, 128.5, 128.5, 127.8, 123.0, 125.0, 122.8, 121.6, 63.9, 40.9, 36.0, 35.9.

[0077] Example 8

[0078] Preparation of cis-1,3-bifunctionalized cyclobutane 5b, the reaction equation is as follows:

[0079] The operation is the same as in Example 1 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), p-methoxybenzenesulfonyl chloride 2h (61.9 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (0.2 mL, 0.0789 mg, 0.0001 mmol), acetonitrile 15.8 mL, and stirred for 12 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow solid 5b (71.8 mg, 75%).

[0080] The NMR data of 5b are as follows:

[0081] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 – 7.88 (m, 2H), 7.77 – 7.72 (m, 1H), 7.68 – 7.64 (m, 1H), 7.60 – 7.54 (m, 1H), 7.51 – 7.44 (m, 4H), 7.39 – 7.34 (m, 1H), 6.52 – 6.43 (m, 2H), 4.30 – 4.17 (m, 3H), 3.52 (s, 3H), 3.20 – 3.10 (m, 2H), 3.07 – 2.97 (m, 2H).

[0082] 13 C NMR (101 MHz, CDCl 3 ) δ 199.0, 174.8, 163.2, 153.1, 135.1, 134.9, 133.5, 131.1, 130.0, 128.8, 128.5, 125.9, 124.8, 122.7, 121.5, 113.6, 64.1, 55.3, 40.8, 35.89, 35.86

[0083] Example 9

[0084] Preparation of cis-1,3-difunctionalized cyclobutane 5c, the reaction equation is as follows:

[0085] The operation is the same as in Example 1 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1a (61.4 mg, 0.2 mmol), p-chlorobenzenesulfonyl chloride 2i (63.3 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (0.2 mL, 0.0789 mg, 0.0001 mmol), acetonitrile 15.8 mL, and stirred for 12 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain white solid 5c (81.8 mg, 85%).

[0086] The NMR data of 5c are as follows:

[0087] 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 – 7.79 (m, 2H), 7.72 – 7.65 (m, 1H), 7.57 – 7.53 (m, 1H), 7.52– 7.46 (m, 1H), 7.43 – 7.36 (m, 4H), 7.36 – 7.30 (m,1H), 7.28 – 7.20 (m, 1H), 6.97 – 6.89 (m, 2H), 4.21 – 4.10 (m, 3H), 3.09 –3.01 (m, 2H), 3.01 – 2.93 (m, 2H).

[0088] 13 C NMR (101 MHz, CDCl 3 ) δ 198.8, 174.3, 152.9, 134.0, 138.2, 134.9, 134.8, 133.5, 129.2, 128.9, 128.7, 128.5, 126.4, 125.3, 122.7, 121.6, 77.4, 77.1, 76.8, 64.0, 40.8, 36.0, 35.8.

[0089] Example 10

[0090] Preparation of cis-1,3-bifunctionalized cyclobutane 6a, the reaction equation is as follows:

[0091] The operation is the same as in Example 1 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1b (68.2 mg, 0.2 mmol), tribromomethane 2b (75.8 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (2 mL, 0.789 mg, 0.001 mmol), acetonitrile 14 mL, and stirred for 10 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow oil 6a (74.6 mg, 73%).

[0092] The NMR data of 6a are as follows:

[0093] 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 – 7.94 (m, 1H), 7.89 – 7.85 (m, 1H), 7.84 – 7.79 (m, 2H), 7.51 – 7.41 (m, 3H), 7.42 – 7.35 (m, 1H), 5.66 (t, J J =6.8 Hz, 1H), 4.13 – 4.00 (m, 1H), 3.44 (d, J J = 6.8 Hz, 2H), 3.12 – 3.05 (m, 2H), 3.03 – 2.95 (m, 2H).

[0094] 13 C NMR (101 MHz, CDCl 3) δ 198.0, 175.9, 152.8, 139.9, 134.9, 133.3, 129.8, 129.2, 126.4, 125.3, 123.0, 121.8, 54.2, 44.4, 40.6, 36.9, 36.4.

[0095] Example 11

[0096] Preparation of cis-1,3-difunctionalized cyclobutane 6b, the reaction equation is as follows:

[0097] The operation is the same as in Example 1 of the present invention. The amounts of reactants used are as follows: 3-methylenecyclobutyl tert-alcohol 1c (61.4 mg, 0.2 mmol), tribromomethane 2b (75.8 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (2 mL, 0.789 mg, 0.001 mmol), acetonitrile 14 mL, and stirred for 10 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow oil 6b (82 mg, 81%).

[0098] The NMR data of 6b are as follows:

[0099] 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J J = 8.0 Hz, 1H), 7.87 (d, J J = 8.0Hz, 1H), 7.51 – 7.34 (m, 5H), 7.15 – 7.06 (m, 1H), 5.69 (t, J J = 6.8 Hz, 1H),4.11 (p, J J = 8.8 Hz, 1H), 3.85 (s, 3H), 3.45 (d, J J = 6.8 Hz, 2H), 3.15 – 3.03(m, 2H), 3.03 – 2.92 (m, 2H).

[0100] 13 C NMR (101 MHz, CDCl 3 ) δ 199.0, 176.0, 160.0, 153.1, 136.4, 135.0, 129.8, 126.3, 125.2, 123.0, 121.8, 121.0, 119.8, 112.7, 55.5, 54.2, 44.3, 40.7, 37.0, 36.5.

[0101] Example 12

[0102] Preparation of cis-1,3-bifunctionalized cyclobutane 6c, the reaction equation is as follows:

[0103] The operation is the same as in Example 1 of the present invention. The amounts of reactants are as follows: 3-methylenecyclobutyl tert-alcohol 1d (62.6 mg, 0.2 mmol), tribromomethane 2b (75.8 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (2 mL, 0.789 mg, 0.001 mmol), acetonitrile 14 mL, and stirred for 10 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow oil 6c (88.8 mg, 92%).

[0104] The NMR data of 6c are as follows:

[0105] 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 – 7.96 (m, 1H), 7.90 – 7.84 (m, 1H), 7.52 – 7.44 (m, 1H), 7.41 – 7.35 (m, 1H), 5.65 (t, J = 6.8 Hz, 1H), 3.54 (p, J = 8.8 Hz, 1H), 3.35 (d, J = 6.8 Hz, 2H), 2.94 – 2.83 (m, 2H), 2.85 – 2.73 (m, 2H), 2.47 – 2.32 (m, 1H), 1.88 – 1.72 (m, 4H), 1.70 – 1.60 (m, 1H), 1.39 – 1.13 (m, 5H).

[0106] 13 C NMR (101 MHz, CDCl 3) δ 212.8, 176.1, 152.9, 134.9, 126.3, 125.2, 123.0, 121.8, 53.9, 49.0, 44.0, 40.7, 37.8, 36.4, 28.5, 25.8, 25.6.

[0107] Example 13

[0108] Preparation of cis-1,3-bifunctionalized cyclobutane 7a, and the reaction equation is as follows:

[0109] The operation is the same as in Example 1 of the present invention. The amounts of reactants used are as follows: 3-methylenecyclobutyl tert-alcohol 1e (51.4 mg, 0.2 mmol), tribromomethane 2b (75.8 mg, 0.3 mmol), organic photocatalyst 4-CzIPN (2 mL, 0.789 mg, 0.001 mmol), acetonitrile 14 mL, and stirred for 10 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 20~10:1, v / v) to obtain a pale yellow solid 7a (64 mg, 75%).

[0110] The NMR data of 7a are as follows:

[0111] 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 – 7.83 (m, 2H), 7.71 (d, J = 3.2 Hz, 1H), 7.59 – 7.52 (m, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 3.2 Hz, 1H), 5.55 (t, J = 6.8 Hz, 1H), 4.09 (p, J = 8.8 Hz, 1H), 3.37 (d, J = 6.8 Hz, 2H), 2.99 – 2.93 (m, 4H).

[0112] 13 C NMR (101 MHz, CDCl 3) δ 199.3, 175.4, 142.9, 135.0, 133.4, 128.8, 128.4, 119.0, 77.4, 77.1, 76.8, 54.4, 43.7, 41.0, 37.3, 36.4.

[0113] Example 14

[0114] Preparation of cis-1,3-difunctionalized cyclobutane 7b, the reaction equation is as follows:

[0115] At room temperature, 3-methylene cyclobutyl tert-alcohol 1f (60.2 mg, 0.2 mmol), additive K 2 HPO4 (34.8 mg, 0.2 mmol), organic photocatalyst 4-CzIPN (1.58 mg, 0.002 mmol), dibromofluoromethane 2j (57.6 mg, 0.3 mmol), and 2 mL of acetonitrile were successively added to a dry 25 mL Schlenk reaction tube filled with a nitrogen atmosphere. After the reaction tube was sealed, it was placed under a 35 W blue LED lamp for irradiation and stirred for 10 hours. After the reaction was completed, the reaction solvent was removed using a rotary evaporator to obtain a crude product, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate 10~5:1, v / v) to obtain white solid 7b (59.6 mg, 88%).

[0116] The NMR data of 7b are as follows:

[0117] 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 – 7.74 (m, 2H), 6.97 – 6.88 (m, 2H), 6.78 – 6.60 (m, 1H), 4.00 (p, J = 8.8 Hz, 1H), 3.85 (s, 3H), 3.13 – 2.84 (m, 3H), 2.73 – 2.65 (m, 1H), 2.65 – 2.58 (m, 1H), 2.54 – 2.44 (m, 1H).

[0118] 13 C NMR (101 MHz, CDCl 3 ) δ196.3, 164.0, 130.7, 127.5, 121.5, 114.1, 90.7 (d, J= 253.5 Hz), 55.6, 47.4 (d, J = 19.2 Hz), 36.0, 34. 5(d, J = 3.0Hz), 34.3, 29.9.

[0119] 19 F NMR (376 MHz, CDCl 3 ) δ -135.50 (m).

[0120] Example 15

[0121] Preparation of cis-1,3-difunctionalized cyclobutane 7c, the reaction equation is as follows:

[0122] The operation is the same as in Example 14 of the present invention. The amounts of reactants used are as follows: 1 g (46.4 mg, 0.2 mmol) of 3-methylenecyclobutyl tert-alcohol, additive K 2 HPO 4 (34.8 mg, 0.2 mmol), organic photocatalyst 4-CzIPN (1.58 mg, 0.002 mmol), dibromofluoromethane 2j (57.6 mg, 0.3 mmol), 2 mL of acetonitrile, stirred for 10 hours. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 8 - 4:1, v / v) to obtain a pale yellow oil 7c (58.8 mg, 86%).

[0123] The NMR data of 7c are as follows:

[0124] 1 1H NMR (400 MHz, CDCl 3 ) δ 9.67 – 9.60 (m, 1H), 7.92 – 7.78 (m, 2H), 6.99 – 6.91 (m, 2H), 6.73 – 6.54 (m, 1H), 4.12 – 3.99 (m, 1H), 3.88 (s, 3H), 3.05 – 2.67 (m, 4H), 2.52 – 2.38 (m, 1H), 2.34 – 2.23 (m, 1H).

[0125] 13 13C NMR (101 MHz, CDCl 3 ) δ 201.1, 197.7, 163.8, 130.7, 127.8, 114.0, 91.8 (d,J = 252.5 Hz), 55.6, 47.1, 45.4 (d, J = 19.2 Hz), 35.8, 29.4 (d, J =2.0 Hz), 29.2.

[0126] 19 F NMR (376 MHz, CDCl 3 ) δ -132.48 (m).

[0127] Example 16

[0128] Preparation of bicyclo[2.1.1]hexane 8a, the reaction equation is as follows:

[0129] Using cis-1,3-bifunctionalized cyclobutane 7a (64 mg, 0.15 mmol) as the starting material, add this starting material and THF (2 mL) to a dry reaction tube filled with a nitrogen atmosphere at room temperature to form a reaction system. Cool the reaction system to 0 °C in an ice-water bath. Under a nitrogen atmosphere, measure KHDMS (0.18 mL, 0.18 mmol) with a long needle syringe and slowly add it dropwise to the reaction system at an average rate of one drop every 3 seconds. Then slowly return to room temperature and continue stirring. Monitor the reaction by TLC until the reaction is complete. After the reaction is completed, add saturated NH 4 Cl aqueous solution to quench the reaction, add organic solvent ethyl acetate for extraction and layering, extract 3 times, combine the organic phases, wash the organic phases with saturated NaCl 3 times, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is separated by column chromatography (petroleum ether / ethyl acetate 10~6:1, v / v) to obtain a pale yellow solid 8a (41.6 mg, 80%).

[0130] The NMR data of 8a are as follows:

[0131] 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 – 7.85 (m, 2H), 7.75 (d, J = 3.2 Hz,1H), 7.62 – 7.55 (m, 1H), 7.51 – 7.44 (m, 2H), 7.30 (d, J= 3.2 Hz, 1H), 4.91– 4.85 (m, 1H), 3.16 – 3.05 (m, 1H), 2.74 – 2.67 (m, 1H), 2.66 – 2.55 (m,3H), 2.48 – 2.39 (m, 1H).

[0132] 13 C NMR (101 MHz, CDCl 3 ) δ 198.5, 169.2, 142.8, 136.4, 133.3, 128.7,128.4, 119.1, 61.6, 51.2, 50.3, 49.0, 45.3, 45.0.

[0133] Example 17

[0134] Preparation of bicyclo[2.1.1]hexane 8b, the reaction equation is as follows:

[0135] Using cis-1,3-bifunctionalized cyclobutane 7b (67.8 mg, 0.2 mmol) as the starting material, add this starting material and THF (2 mL) to a dry reaction tube filled with a nitrogen atmosphere at room temperature to form a reaction system. Cool the reaction system to 0 °C in an ice-water bath. Under a nitrogen atmosphere, measure LiHDMS (0.21 mL, 0.21 mmol) with a long needle syringe and slowly add it dropwise to the reaction system at an average rate of one drop every 3 seconds. Then slowly return to room temperature and continue stirring. Monitor the reaction by TLC until the reaction is complete. After the reaction is completed, add saturated NH 4 Cl aqueous solution to quench the reaction, add organic solvent ethyl acetate for extraction and layering, extract 3 times, combine the organic phases, wash the organic phases 3 times with saturated NaCl, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is separated by column chromatography (petroleum ether / ethyl acetate 8~4:1, v / v) to obtain a pale yellow oil 8b (45.6 mg, 88%).

[0136] The NMR data of 8b are as follows:

[0137] 1 H NMR (400 MHz, CDCl 3) δ 7.89 – 7.78 (m, 2H), 6.99 – 6.90 (m, 2H), 5.54 – 5.30 (m, 1H), 3.88 (s, 3H), 2.75 – 2.60 (m, 2H), 2.60 – 2.54 (m, 1H), 2.45 – 2.37 (m, 1H), 2.32 – 2.18 (m, 1H), 2.18 – 2.09 (m, 1H).

[0138] 13 C NMR (101 MHz, CDCl 3 ) δ 195.5, 164.1, 131.28, 131.26, 128.7, 118.5, 114.0, 93.0, (d, J = 197.0 Hz), 61.4 (d, J = 21.2 Hz), 55.6, 47.3 (d, J = 5.1Hz), 43.4 (d, J = 2.0 Hz), 40.9 (d, J = 22.2 Hz), 31.2(d, J = 2.0 Hz).

[0139] 19 F NMR (376 MHz, CDCl 3 ) δ -176.84 (m).

[0140] Example 18

[0141] Preparation of bicyclo[2.1.1]hexane 8c, the reaction equation is as follows:

[0142] Using cis-1,3-bifunctionalized cyclobutane 7c (68.4 mg, 0.2 mmol) as the starting material, add this starting material and THF (2 mL) to a dry reaction tube filled with a nitrogen atmosphere at room temperature to form a reaction system. Cool the reaction system to 0 °C in an ice-water bath. Under a nitrogen atmosphere, use a long needle syringe to measure LiHDMS (0.21 mL, 0.21 mmol) and slowly add it dropwise to the reaction system at an average rate of one drop every 3 seconds. Then slowly warm back to room temperature and continue stirring. Monitor the reaction by TLC until the reaction is complete. After the reaction is completed, add saturated NH 4The reaction was quenched with an aqueous solution of Cl, and ethyl acetate, an organic solvent, was added for extraction and layering. The extraction was carried out 3 times, and the organic phases were combined. The combined organic phase was washed 3 times with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate 6~2:1, v / v) to obtain a pale yellow solid 8c (39.3 mg, 75%).

[0143] The NMR data of 8c are as follows:

[0144] 1 H NMR (400 MHz, CDCl 3 ) δ 9.75 (s, 1H), 7.97 – 7.78 (m, 2H), 7.00 – 6.83 (m, 2H), 5.58 – 5.34 (m, 1H), 3.87 (s, 3H), 2.63 – 2.38 (m, 3H), 2.35 – 2.26 (m, 1H), 2.19 – 2.02 (m, 1H), 2.03 – 1.92 (m, 1H).

[0145] 13 C NMR (101 MHz, CDCl 3 ) δ 199.1, 197.0, 163.8, 131.3 (d, J = 2.0 Hz), 129.1, 113.9, 94.4 (d, J = 195.9 Hz), 60.6 (d, J = 21.2 Hz), 55.5, 54.0, 44.4 (d, J = 5.1 Hz), 40.6 (d, J = 2.0 Hz), 37.3 (d, J = 22.2 Hz).

[0146] 19 F NMR (376 MHz, CDCl 3 ) δ -175.95 (m).

[0147] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be recognized that the above description should not be considered as a limitation of the present invention. After those skilled in the art have read the above content, various modifications and alternatives to the present invention will be obvious. Therefore, the protection scope of the present invention should be defined by the appended claims.

Claims

1. A cis-1, 3-difunctionalized cyclobutane compound of single configuration, characterized in that: The general structural formula is shown in formula (I): Formula (I) Where: R 1 is selected from phenyl, substituted phenyl or cyclohexyl, wherein the substituent on the phenyl ring of the substituted phenyl is C1-C4 alkyl, C1-C4 alkoxy or halogen; R 2 is a C1 - C8 alkyl group, a fluorinated alkyl group, an acyl group, or a sulfonyl group; FG is a thiazole, a benzothiazole, a thiophene, a benzofuran, an oxime group, a cyano group, or an aldehyde group.

2. A method for synthesizing a single-configuration cis-1, 3-difunctionalized cyclobutane compound as claimed in claim 1, characterized in that: The method comprises the following steps: adding 3-methylenecyclobutyl tertiary alcohol, any one of alkyl halide, acyl halide and sulfonyl halide, and a photocatalyst to an organic solvent; reacting under nitrogen atmosphere and irradiation with a blue LED lamp, stirring at room temperature for 8 to 24 hours, and generating a single-configuration cis-1, 3-difunctionalized cyclobutane. The reaction process is shown in formula (II): Formula (II) Where: R 1 is selected from phenyl, substituted phenyl or cyclohexyl, wherein the substituent on the phenyl ring of the substituted phenyl is C1-C4 alkyl, C1-C4 alkoxy or halogen, and R 2 is C1-C8 alkyl, fluorinated alkyl, acyl, sulfonyl. FG is thiazole, benzothiazole, thiophene, benzofuran, oxime, cyano, aldehyde.

3. The preparation method according to claim 2, characterized in that: When the halogenating agent is an alkyl halide, the molar ratio of 3-methylenecyclobutyl tertiary alcohol, alkyl halide and photocatalyst is 1:1.2-1.5:0.001-0.02, preferably 1:1.5:0.005; when the halogenating agent is an acyl halide, the molar ratio is 1:2:0.01-0.02, preferably 1:2:0.02; when the halogenating agent is a sulfonyl halide, the molar ratio is 1:2:0.0005-0.01, preferably 1:2:0.0005.

4. The preparation method according to claim 2, characterized in that: The reaction is carried out in an organic solvent, and the organic solvent is selected from one of acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, chlorobenzene, 1, 4-dioxane, and N,N-dimethylformamide, preferably acetonitrile.

5. The preparation method according to claim 2, characterized in that: The amount of the solvent used in the reaction is 1 - 80 mL / mmol.

6. The preparation method according to claim 2, characterized in that: The reaction requires a blue LED light with a wavelength of 450 to 460 nm.

7. The preparation method according to claim 2, characterized in that: The organic photocatalyst is 4-CzIPN, f One of ac-Ir(ppy)3, Ir(dtbbpy)(ppy)2PF6, Rhodamine B, and Rose Bengal, preferably 4-CzIPN.

8. The preparation method according to claim 2, characterized in that: The reaction is carried out in an anhydrous and oxygen-free environment protected by nitrogen and stirred at room temperature for 8 to 24 hours.

9. A polysubstituted bicyclo[2.1.1]hexane, characterized in that The general structural formula is shown in formula (III): Formula (III) Wherein: FG is thiazole, benzothiazole, thiophene, benzofuran, oxime, cyano, or aldehyde; Ar is selected from phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is p-methoxy; and X is selected from fluorine atom or bromine atom.

10. A method for synthesizing a polysubstituted bicyclo[2.1.1]hexane as claimed in claim 9, characterized in that: The method comprises the following steps: using the obtained cis-1, 3-difunctionalized cyclobutane as a starting material, adding the starting material and tetrahydrofuran as a reaction solvent in a dry reaction tube filled with nitrogen atmosphere at room temperature to form a reaction system; placing the reaction system in an ice-water bath and cooling it to 0°C. Under a nitrogen atmosphere, adding a base to the reaction system at an average rate of one drop per 3 seconds, and the dropping speed helps to control the reaction rate and selectivity. Then slowly returning to room temperature and continuing stirring. TLC (thin layer chromatography) monitors the reaction until the reaction is completed. After the reaction is completed, adding a saturated NH4Cl aqueous solution to quench the reaction, adding an organic solvent ethyl acetate to extract and separate the layers; taking the organic layer, drying it with anhydrous sodium sulfate, filtering it, and concentrating it to obtain a crude product, and the crude product is separated by column chromatography to obtain the target product multi-substituted bicyclo[2.1.1]hexane. The reaction process is shown in formula (IV): Formula (IV) Wherein: FG is thiazole, benzothiazole, thiophene, benzofuran, oxime, cyano, or aldehyde; Ar is selected from phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is p-methoxy; and X is selected from fluorine atom or bromine atom.

11. The preparation method according to claim 10, characterized in that: The molar ratio of the starting material cis-1,3-difunctionalized cyclobutane to the added base is 1:1.05-1.2, and the added base is selected from one of bis(trimethylsilyl) potassium amide or bis(trimethylsilyl) lithium amide. When X is a bromine atom, bis(trimethylsilyl) potassium amide is preferred; when X is a fluorine atom, bis(trimethylsilyl) lithium amide is preferred.

12. The preparation method according to claim 10, characterized in that: The reaction temperature was first stirred at 0 °C for 0.5 hours, then slowly returned to room temperature and continued stirring for 1-2 hours until the reaction was completed.

13. The preparation method according to claim 10, characterized in that: The reaction is carried out in an anhydrous and oxygen-free environment protected by nitrogen, with tetrahydrofuran as the reaction solvent.

14. The preparation method according to claim 10, characterized in that: After the reaction, the reaction is performed with a mixed solvent of petroleum ether and ethyl acetate for column chromatography, and the ratio of the eluents of petroleum ether and ethyl acetate is adjusted in due time according to the separation effect.

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