Process for the preparation of compounds having a methylenecyclobutane structure and process for the preparation of derived dimethylmethylenecyclobutane compounds

Abstract

The application discloses a preparation method of a compound with a methylenecyclobutane structure and a preparation method of a derivative dimethyl methylenecyclobutane compound. The application develops a method for constructing and separating a methylenecyclobutane compound containing a borate functional group in one step through transition metal catalytic borization and cyclization by taking an easily-prepared aliphatic alkyne compound as a starting material. The methylenecyclobutane compound is subjected to various functional group transformations through simple chemical reactions, and various functional group-containing cyclobutane compounds are prepared. The synthesis method provided by the application has the advantages of easy preparation of raw materials, high atom economy, easy separation, wide application and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to methods for preparing compounds containing methylenecyclobutane and methods for preparing dimethylcyclobutane compounds derived therefrom. Compounds containing dimethylcyclobutane are useful intermediates for the synthesis of insect sex pheromones. Background Technology

[0002] Compounds with a methylenecyclobutane skeleton are not only the basic structures of some natural products but also an important class of organic synthetic intermediates. They exhibit unusual chemical reactivity and are therefore widely used in synthetic chemistry. Incorporating strained rings into drug candidates can significantly alter their structural rigidity and spatial conformation, leading to substantial changes in their physicochemical and pharmacokinetic properties, such as metabolic stability, lipophilicity, and solubility, thereby enhancing their drug activity. Furthermore, the derived dimethylmethylenecyclobutane compounds can be used to synthesize insect sex pheromones.

[0003] Insect sex pheromones are biologically active compounds, typically trace amounts of chemicals secreted by insects to attract individuals of the same species to mate. They constitute a species-specific communication system. In agriculture, they can be used to detect, monitor, attract, and kill certain types of pests.

[0004] Currently, the primary means of pest control in agricultural production still relies on chemical pesticides. However, the long-term, uncontrolled use of chemical pesticides has brought many side effects. First, the development of pesticide resistance in pests leads to continuously increasing dosages and concentrations, raising costs year by year and making control increasingly difficult. Second, it disrupts the ecological balance; while controlling pests, a large number of natural enemies are killed, causing rampant secondary pests. Third, it pollutes the environment; large amounts of pesticide residues remain in crops, soil, rivers, lakes, and seas, and accumulate in humans through the food chain, posing further harm. Therefore, research departments both domestically and internationally are actively exploring and researching new approaches and technologies for pest control, including the application of insect hormones. Research on the use of insect hormones, especially sex pheromones, for pest control is receiving increasing attention and importance.

[0005] Among the various types of sex pheromones, one unique chemical structure is the dimethylmethylenecyclobutane structure. However, common methods for preparing pheromones with these dimethylcyclobutane structures typically use pinene as a raw material, synthesizing these pheromones through a complex series of chemical reactions. These reactions involve the participation of heavy metals, causing significant environmental pollution; moreover, certain reaction conditions pose substantial safety hazards and are extremely unsuitable for industrial practice.

[0006] Therefore, there is an urgent need to develop a synthetic method that is simple to operate, highly atom-economical, easy to separate, and more widely applicable for use in research on the pharmaceutical activity and agricultural applications of pheromones with a dimethylcyclobutane structure. Summary of the Invention

[0007] The purpose of this invention is to provide methods for preparing compounds having a methylenecyclobutane structure and methods for preparing derived dimethylmethylenecyclobutane compounds. Furthermore, these methods are simple to operate, economical, environmentally friendly, and efficient.

[0008] To achieve the above objectives, the technical solution of the present invention is as follows:

[0009] A method for synthesizing methylene cyclobutane derivatives with borate ester functional groups, using compound 1 as a raw material, reacting with a catalyst and additives in a solvent under the protection of inert argon gas to generate the target product;

[0010] The reaction route is shown in equation (1) below:

[0011]

[0012] Wherein, R1, R2, R3 and R4 are aliphatic hydrocarbon groups or aromatic hydrocarbon groups with no more than 18 carbon atoms; the LG group is a leaving group; the additives are pinacol diboronic acid ester and base; the reaction time is 12 to 24 hours.

[0013] Preferably, the catalyst is a copper salt.

[0014] Preferably, the alkali is any one of sodium methoxide, lithium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and potassium tert-pentoxide.

[0015] Preferably, the molar ratio of compound 1 to copper salt, pinacol diboronic acid ester, and base is 1:(0.05-0.20):(1.0-2.0):(0.20-2.0).

[0016] Preferably, the solvent is any one of tetrahydrofuran (THF), benzene, toluene, DMF, DMA, and DCM.

[0017] The present invention also provides a method for synthesizing methylene cyclobutane derivatives with other functional groups, using compound 2 as a raw material, adding additives and reacting in a solvent under the protection of inert gas argon to generate the target product;

[0018] The reaction route is shown in equation (2) below:

[0019]

[0020] Wherein, R1, R2, R3, R4 and R5 are aliphatic hydrocarbon groups, aromatic hydrocarbon groups or heteroatomic groups with no more than 18 carbon atoms; Bpin is pinacol borate ester; the reaction time is 3-24 hours.

[0021] Preferably, the additive is any one or a combination of several of the following: metal catalyst, alkali, oxidant, acylation reagent, olefination reagent, alkyne compound, and aryl halide.

[0022] Preferably, the catalyst is a palladium or copper catalyst.

[0023] Preferably, the alkali is any one or a combination of several of the following: sodium azide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium perborate hydrate, potassium carbonate, potassium hydrofluoric acid, morpholine, sodium ascorbate, methyltriphenylphosphine bromide, potassium iodide, p-toluenesulfonyl chloride, n-butyllithium, and pyridine.

[0024] Preferably, the oxidant is m-chloroperoxybenzoic acid, hydrogen peroxide, or a combination thereof;

[0025] Preferably, the acylation reagent is a hydrocarbon carboxylic acid, acyl chloride, or acid anhydride compound with no more than 10 carbon atoms.

[0026] Preferably, the olefinizing agent is a trialkyl phosphonoacetate with no more than 10 carbon atoms.

[0027] Preferably, the alkyne compound is an alkyne compound with various functional groups and no more than 20 carbon atoms.

[0028] Preferably, the aryl halide is an aromatic compound containing bromine, chlorine, or iodine or a combination thereof, with no more than 20 carbon atoms.

[0029] Preferably, the ratio of compound 2 to additive is 1:(0.05-10.0).

[0030] Preferably, the solvent is any one or a combination of several of tetrahydrofuran (THF), benzene, toluene, DMF, DMA, DCM, acetonitrile, water, deuterium water, methanol, tert-butanol, and ammonia water.

[0031] Compared with the prior art, the present invention has the following advantages:

[0032] 1) The conditions are mild, the required reagents are inexpensive and commercially available, and it is compatible with a variety of functional groups, making it more widely applicable;

[0033] 2) The raw materials used in the reaction can be converted into products in high yield with only 1-4 simple chemical reactions, which greatly reduces the number of reaction steps;

[0034] 3) In the preparation of two insect sex pheromones, the traditional method uses pinene as a raw material and synthesizes these pheromones through a series of complex chemical reactions. These reactions involve the participation of some heavy metals, which not only causes significant environmental pollution, but also poses significant safety hazards under certain reaction conditions, making them extremely unsuitable for industrial practice. In contrast, this invention can prepare these sex pheromones through a simple chemical reaction, avoiding the use of potentially hazardous organic reagents and precious metal reagents. It is economical, environmentally friendly, and has high atom economy, and the reaction operation is simple and easy to separate and purify. Detailed Implementation

[0035] In the chemical formulas of the intermediates, reagents, and target compounds described in this specification, there may be some isomers or stereoisomers with different substitution positions in structure, such as enantiomers or diastereomers. Unless otherwise stated, in each case, each chemical formula should be interpreted as representing all such isomers. Furthermore, these isomers can be isomers or combinations thereof. To enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to preferred embodiments.

[0036] Example 1.1: Synthesis of 2-(cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane compound (2a):

[0037]

[0038] When the leaving group LG is -OMs, in an argon-filled glove box, a magnetic sample was transferred to a 5 mL Schlenk flask, and cuprous chloride (2.0 mg, 0.02 mmol, 0.10 eq), potassium tert-butoxide (26.9 mg, 0.24 mmol, 1.20 eq), and tetrahydrofuran (0.5 mL) were added. After stirring the mixture for ten minutes, B2pin2 (61 mg, 0.24 mmol, 1.2 eq), substrate 1a (0.20 mmol), and the solvent tetrahydrofuran (0.5 mL) were added. The flask was then sealed and removed from the glove box. The reaction mixture was stirred at 50°C for 24 hours, after which the reaction was stopped. To separate the product, the volatiles were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 27.9 mg of product 2a, in 72% yield. 1 H NMR (400MHz, CDCl3) δ5.08 (t, J = 2.4 Hz, 1H), 2.96–2.86 (m, 2H), 2.81–2.72 (m, 2H), 1.95 (p, J = 8.0 Hz, 2H), 1.24 (s, 12H).

[0039] Example 1.2: Synthesis of 4,4,5,5-tetramethyl-2-(3-methylcyclobutyl)methyl)-1,3,2-dioxaborane (2b):

[0040]

[0041] The reaction procedure was the same as that in Example 1, except that the reactant was 1b, the leaving group was -OTs, the copper salt was cuprous bromide (5.6 mg, 0.04 mmol, 0.2 eq), the base was sodium tert-butoxide (9.6 mg, 0.1 mmol, 0.5 eq), the pinacol diborate was pinacol ester (70.6 mg, 0.3 mmol, 1.5 eq), the solvent was DMF (2 mL), the reaction temperature was room temperature, and the reaction time was 12 hours. The pure product was obtained by column chromatography in 70% yield. 1 H NMR (400MHz, CDCl3) δ5.11(t,J=2.4Hz,1H),3.17–2.97(m,1H),2.94–2.79(m,1H),2.56–2.20(m,3H),1.23(s,12H),1.13(d,J=6.4Hz,3H).

[0042] Example 1.3: Synthesis of 2-((3-butylcyclobutyl)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2c):

[0043]

[0044] The reaction procedure was the same as that in Example 1, except that the reactant was 1c, the leaving group was -Br, the copper salt was cuprous iodide (5.7 mg, 0.03 mmol, 0.15 eq), the base was sodium methoxide (16.2 mg, 0.3 mmol, 1.5 eq), the solvent was pinacol diboronate (50.8 mg, 0.2 mmol, 1.0 eq), the solvent was DMA (1.5 mL), the reaction temperature was 80°C, and the reaction time was 20 hours. The pure product was obtained by column chromatography in 76% yield. 1 H NMR (400MHz, CDCl3) δ5.13–5.07(m,1H),3.07–2.96(m,1H),2.86–2.76(m,1H),2.50–2.42(m,1H),2.39–2. 32(m,1H),2.23(dq,J=15.2,7.6Hz,1H),1.45(q,J=7.6Hz,2H),1.33–1.22(m,16H),0.88(t,J=7.2Hz,3H).

[0045] Example 1.4: Synthesis of 4,4,5,5-tetramethyl-2-(3-phenylcyclobutylmethyl)-1,3,2-dioxaborane (2d):

[0046]

[0047] The reaction procedure was the same as that in Example 1, except that the reactant was 1d, the leaving group was -OTs, the copper salt was cuprous acetate (1.2 mg, 0.01 mmol, 0.05 eq), the base was potassium methoxide (18.2 mg, 0.26 mmol, 1.3 eq), the solvent was pinacol diboronate (66 mg, 0.26 mmol, 1.3 eq), the solvent was DCM (1.5 mL), the reaction temperature was 70°C, and the reaction time was 21 hours. The pure product was obtained by column chromatography in 63% yield. 1 H NMR (400MHz, CDCl3) δ7.35–7.24(m,4H),7.19(t,J=6.8Hz,1H),5.22(s,1H),3.55(p,J=8.4Hz, 1H),3.45–3.35(m,1H),3.22–3.12(m,1H),3.08–2.99(m,1H),2.98–2.90(m,1H),1.25(s,12H).

[0048] Example 1.5: Synthesis of 4,4,5,5-tetramethyl-2-(3-(p-tolyl)cyclobutylmethyl)-1,3,2-dioxaborane (2e):

[0049]

[0050] The reaction procedure was the same as that in Example 1, except that the reactant was 1e, the copper salt was cuprous bromide (2.3 mg, 0.016 mmol, 0.08 eq), the base was potassium tert-amyloxide (41.0 mg, 0.32 mmol, 1.6 eq), and pinacol diboronate (55.9 mg, 0.22 mmol, 1.1 eq), the solvent was THF (1 mL), the reaction temperature was 60°C, and the reaction time was 22 hours. The pure product was obtained by column chromatography in 75% yield. 1 H NMR (400MHz, CDCl3) δ7.17(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),5.22(p,J=2.0Hz,1H),3.52(p,J=8.0Hz, 1H),3.43–3.34(m,1H),3.20–3.11(m,1H),3.06–2.97(m,1H),2.96–2.88(m,1H),2.33(s,3H),1.26(s,12H).

[0051] Example 1.6: Synthesis of 2-((3-(4-methoxyphenyl)cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2f):

[0052]

[0053] The reaction procedure was the same as that in Example 1, except that the reactants were 1f, the copper salt was cuprous chloride (3.0 mg, 0.3 mmol, 0.15 eq), the base was sodium methoxide (18.2 mg, 0.26 mmol, 1.3 eq), the pinacol diborate was pinacol ester (55.9 mg, 0.22 mmol, 1.1 eq), the solvent was toluene (0.5 mL), the reaction temperature was 55°C, and the reaction time was 18 hours. The pure product was obtained by column chromatography in 72% yield. 1 H NMR (400MHz, CDCl3) δ7.19(d,J=8.4Hz,2H),6.85(d,J=8.8Hz,2H),5.22(p,J=2.0Hz,1H),3.79(s,3H),3.49 (p,J=8.4Hz,1H),3.42–3.33(m,1H),3.19–3.10(m,1H),3.03–2.95(m,1H),2.93–2.85(m,1H),1.26(s,12H).

[0054] Example 1.7: Synthesis of 4,4,5,5-tetramethyl-2-(3-(4-(trifluoromethyl)phenyl)cyclobutylmethyl)-1,3,2-dioxaborane (2g):

[0055]

[0056] The reaction procedure was the same as that in Example 1, except that the reactant was 1 g, the copper salt was copper acetate (3.2 mg, 0.016 mmol, 0.08 eq), the base was lithium tert-butoxide (6.4 mg, 0.08 mmol, 0.4 eq), pinacol diborate (91.4 mg, 0.36 mmol, 1.8 eq), the solvent was benzene (2.5 mL), the reaction temperature was 75 degrees Celsius, and the reaction time was 21 hours. The pure product was obtained by column chromatography in 61% yield. 1HNMR (400MHz, CDCl3) δ7.56(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),5.25(s,1H),3.60(p,J=8.0H z,1H),3.49–3.39(m,1H),3.26–3.16(m,1H),3.08–2.99(m,1H),2.98–2.89(m,1H),1.26(s,12H).

[0057] Example 1.8: Synthesis of 2-(3-(4-chlorophenyl)cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2h):

[0058]

[0059] The reaction procedure was the same as in Example 1, except that the reactants were reactants for 1 hour, the copper salt was copper bromide (5.4 mg, 0.024 mmol, 0.12 eq), the base was lithium methoxide (9.9 mg, 0.26 mmol, 1.3 eq), the reaction product was pinacol diboronate (101.6 mg, 0.4 mmol, 2.0 eq), the solvent was THF (1 mL), the reaction temperature was 90°C, and the reaction time was 20 hours. The pure product was obtained by column chromatography in 70% yield. 1 H NMR (400MHz, CDCl3) δ7.28–7.25(m,2H),7.19(d,J=8.4Hz,2H),5.23(p,J=2.4Hz,1H),3.58–3.45( m,1H),3.46–3.32(m,1H),3.23–3.10(m,1H),3.04–2.92(m,1H),2.93–2.83(m,1H),1.25(s,12H).

[0060] Example 1.9: Synthesis of 2-(3-(4-bromophenyl)cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2i):

[0061]

[0062] The reaction procedure was the same as that in Example 1, except that the reactants were 1i, the copper salt was copper iodide (7.7 mg, 0.04 mmol, 0.2 eq), the base was lithium methoxide (9.1 mg, 0.24 mmol, 1.2 eq), the pinacol diborate was pinacol ester (60.9 mg, 0.24 mmol, 1.2 eq), the solvent was DMA (1 mL), the reaction temperature was 75 degrees Celsius, and the reaction time was 23 hours. The pure product was obtained by column chromatography in 68% yield. 1H NMR (400MHz, CDCl3) δ7.42(d,J=8.4Hz,2H),7.14(d,J=8.4Hz,2H),5.23(p,J=2.4Hz,1H),3.50(p,J=8 .4Hz,1H),3.44–3.34(m,1H),3.21–3.12(m,1H),3.02–2.94(m,1H),2.92–2.84(m,1H),1.25(s,12H).

[0063] Example 1.10: Synthesis of 2-(3-(3-methoxyphenyl)cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2j):

[0064]

[0065] The reaction procedure was the same as that in Example 1, except that the reactant was 1j, the copper salt was copper chloride (4 mg, 0.04 mmol, 0.2 eq), the base was potassium tert-butoxide (33.6 mg, 0.3 mmol, 1.5 eq), and the pinacol diborate was pinacol ester (71.1 mg, 0.28 mmol, 1.4 eq). The solvent was THF (1 mL), the reaction temperature was 60 degrees Celsius, and the reaction time was 23 hours. The pure product was obtained by column chromatography in 75% yield. 1 HNMR (400MHz, CDCl3) δ7.22(t,J=8.0Hz,1H),6.86(d,J=7.6Hz,1H),6.82(d,J=2.0Hz,1H),6.74(dd,J=8.0,2.0Hz,1H),5.22(p,J=2.4 Hz,1H),3.80(s,3H),3.53(p,J=8.4Hz,1H),3.43–3.33(m,1H),3.20–3.10(m,1H),3.07–2.99(m,1H),2.98–2.90(m,1H),1.25(s,12H).

[0066] Example 1.11: Synthesis of 2-(3-(2-methoxyphenyl)cyclobutylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2k):

[0067]

[0068] The reaction procedure was the same as that in Example 1, except that the reactants were 1K, the copper salt was cuprous chloride (2.0 mg, 0.02 mmol, 0.1 eq), the base was sodium tert-butoxide (28.8 mg, 0.3 mmol, 1.5 eq), pinacol diborate (66.0 mg, 0.28 mmol, 1.3 eq), the solvent was toluene (1.0 mL), the reaction temperature was 95 degrees Celsius, and the reaction time was 16 hours. The pure product was obtained by column chromatography in 63% yield. 1 H NMR (400MHz, CDCl3) δ7.31(d,J=7.6Hz,1H),7.20(t,J=6.0Hz,1H),7.18–7.11(m,2H),5.23(s,1H),3.66(p,J=8. 4Hz,1H),3.45–3.32(m,1H),3.21–3.10(m,1H),3.08–3.00(m,1H),2.99–2.90(m,1H),2.28(s,3H),1.27(s,12H).

[0069] Example 12: Synthesis of 4,4,5,5-tetramethyl-2-(3-(naphth-1-yl)cyclobutylmethyl)-1,3,2-dioxaborane (2l):

[0070]

[0071] The reaction procedure was the same as that in Example 1, except that the reactants were 1 L, the copper salt was copper chloride (2.6 mg, 0.026 mmol, 0.13 eq), the base was lithium tert-butoxide (12.8 mg, 0.16 mmol, 0.8 eq), and the pinacol diborate was pinacol ester (76.2 mg, 0.3 mmol, 1.5 eq), the solvent was DMF (0.5 mL), the reaction temperature was 55°C, and the reaction time was 21 hours. The pure product was obtained by column chromatography in 70% yield. 1 H NMR(400MHz, CDCl3) δ7.96(d,J=7.6Hz,1H),7.92–7.83(m,1H),7.73(d,J=7.2Hz,1H),7.58–7.40(m,4H),5.28( s,1H),4.18(p,J=8.4Hz,1H),3.63–3.52(m,1H),3.40–3.28(m,1H),3.27–3.07(m,2H),1.28(d,J=3.2Hz,12H).

[0072] Example 1.13: Synthesis of 2-(3-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-methylene)cyclobutyl)-1H-indole-1-carboxylic acid tert-butyl ester (2m):

[0073]

[0074] The reaction procedure was the same as that in Example 1, except that the reactants were 1 mg, the copper salt was cuprous chloride (1 mg, 0.01 mmol, 0.05 eq), the base was potassium tert-butoxide (29.1 mg, 0.26 mmol, 1.3 eq), and the solvent was pinacol diborate (50.8 mg, 0.2 mmol, 1.0 eq). The reaction temperature was 85°C, and the reaction time was 17 hours. The pure product was obtained by column chromatography in 71% yield. 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.49(d,J=7.6Hz,1H),7.39(s,1H),7.36–7.27(m,1H),7.27–7.18(m,1H),5.28–5.22(m,1H) ,3.68(p,J=7.6Hz,1H),3.51–3.41(m,1H),3.33–3.20(m,1H),3.17–3.06(m,1H),3.05–2.95(m,1H),1.67(s,9H),1.26(s,12H).

[0075] Example 1.14: Synthesis of tert-butyldimethyl((3-((4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)methylene)cyclobutyl)methoxy)silane (2n):

[0076]

[0077] The reaction procedure was the same as that in Example 1, except that the reactants were In, the copper salt was cuprous bromide (2.3 mg, 0.016 mmol, 0.08 eq), the base was sodium tert-butoxide (26.9 mg, 0.28 mmol, 1.4 eq), and the borane diborate was pinacol ester (55.9 mg, 0.22 mmol, 1.1 eq). The solvent was DCM (1.2 mL), the reaction temperature was 90 degrees Celsius, and the reaction time was 22 hours. The pure product was obtained by column chromatography in 85% yield. 1 H NMR(400MHz, CDCl3)δ5.15–5.10(m,1H),3.62(dd,J=6.4,2.0Hz,2H),3.01–2.89(m,1H),2.84 –2.72(m,1H),2.67–2.56(m,1H),2.54–2.42(m,2H),1.24(s,12H),0.89(s,9H),0.05(s,6H).

[0078] The preparation methods for other methylene cyclobutane derivatives are the same as those in Examples 1.1-14, and the products and their yields are shown in Table 1.

[0079] Table 1 Different products and their yields

[0080]

[0081] Example 2.1: Synthesis of methylenecyclobutane compound (3-1) containing iodine functional group:

[0082]

[0083] Under an argon atmosphere, compound 2-1 (0.2 mmol, 60 mg, 1.0 eq), cuprous oxide (0.02 mmol, 3 mg, 0.1 eq), potassium iodide (2.0 mmol, 332 mg, 10.0 eq), and ammonia (1.0 mmol, 5.0 eq) were added to a 5 mL vial. The mixture was stirred at 50°C for 20 hours. After the reaction was complete, to separate the product, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-1 in 62% yield. 1 H NMR (400MHz, CDCl3) δ7.19(t,J=8.0Hz,2H),6.91–6.84(m,2H),5.84(p,J=2.4Hz,0.66H),4.84(p,J=2.4Hz, 0.34H), 3.81 (s, 3H), 3.48 (p, J = 8.0Hz, 1H), 3.18–3.04 (m, 1.32H), 3.03–2.91 (m, 0.68H), 2.87–2.59 (m, 2H).

[0084] Example 2.2: Synthesis of methylenecyclobutane compound (3-2) containing bromine functional group:

[0085]

[0086] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq) and cuprous bromide (1.0 mmol, 143 mg, 5.0 eq) were added to a 5 mL vial in a methanol-water solution (1:1 v / v). The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature. To separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-2 in 74% yield. 1H NMR(400MHz, CDCl3) δ7.19(d,J=8.4Hz,2H),6.87(d,J=8.8Hz,2H),5.92–5.86(m ,1H),3.81(s,3H),3.52(p,J=8.4Hz,1H),3.16–3.05(m,2H),2.84–2.63(m,2H).

[0087] Example 2.3: Synthesis of a chlorine-functionalized methylene cyclobutane compound (3-3):

[0088]

[0089] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq) and cuprous chloride (0.6 mmol, 60 mg, 3.0 eq) were added to a 5 mL vial in a methanol-water solution (2:1 v / v). The mixture was stirred at 80 °C for 18 hours. After the reaction was complete, the mixture was cooled to room temperature. To separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-3 in 70% yield. 1 H NMR (400MHz, CDCl3) δ7.19(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),5.83(s,1 H), 3.81 (s, 3H), 3.53 (p, J = 8.0Hz, 1H), 3.24–3.03 (m, 2H), 2.88–2.72 (m, 2H).

[0090] Example 2.4: Synthesis of methylene cyclobutane compounds (3-4) containing carbonyl functional groups:

[0091]

[0092] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq) and sodium perborate (2.0 mmol, 200 mg, 10.0 eq) were added to a 5 mL vial in 1 mL of tetrahydrofuran-water solution (9:1 v / v). The mixture was stirred at room temperature for 10 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-4 in 66% yield. 1H NMR (400MHz, CDCl3) δ9.95(d,J=1.6Hz,0.5H),9.73(d,J=2.0Hz,0.5H),7.15(t,J=8.0Hz,2H),7.00–6.71(m,2H),3.80( s,1.5H),3.79(s,1.5H),3.59–3.45(m,1H),3.23–3.08(m,1H),2.75–2.64(m,1H),2.59–2.48(m,1H),2.41–2.26(m,2H).

[0093] Example 2.5: Synthesis of methylenecyclobutane compounds (3-5) containing aldehyde functional groups:

[0094]

[0095] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq) and sodium azide (1.0 mmol, 65 mg, 2.5 eq) were added to a 5 mL vial in 0.5 mL of methanol. The mixture was stirred at 50 °C for 15 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-5 in 74% yield. 1 H NMR (400MHz, CDCl3) δ7.18(d,J=8.4Hz,2H),6.86(d,J=8.8Hz,2H),5.85(p,J=2.4 Hz, 1H), 3.80 (s, 3H), 3.54 (p, J = 8.4Hz, 1H), 3.20–3.01 (m, 2H), 2.83–2.74 (m, 2H).

[0096] Example 2.6: Synthesis of methylenecyclobutane compounds (3-6) containing triazole functional groups:

[0097]

[0098] Compound 3-5 (0.2 mmol, 43 mg, 1.0 eq), anhydrous copper sulfate (0.02 mmol, 3.2 mg, 0.1 eq), and sodium ascorbate (0.02 mmol, 4.0 mg, 0.1 eq) were added to a 5 mL vial in 2 mL of tert-butanol-water solution (3:1 v / v). This was then reacted with another reactant, an alkyne compound S1 (0.2 mmol, 59 mg, 1.0 eq), and stirred at room temperature for 12 hours. After the reaction was complete, to separate the products, volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-6 in 78% yield. 1H NMR (400MHz, CDCl3) δ7.49(s,1H),7.22(d,J=8.8Hz,2H),7.09–7.00(m,2H),6.88(d,J=8.4Hz,2H),6.59( dd,J=8.4,2.5Hz,1H),6.56–6.54(m,1H),3.81(s,3H),3.75–3.64(m,1H),3.51–3.40(m,1H),3.35–3.26( m,1H),3.23–3.12(m,1H),3.09–2.98(m,1H),2.85–2.73(m,2H),2.50–2.40(m,1H),2.18–2.07(m,2H),1. 99–1.83(m,3H),1.69–1.55(m,2H),1.50–1.36(m,2H),1.36–1.23(m,2H),1.04(s,3H),0.79–0.66(m,1H).

[0099] Example 2.7: Synthesis of methylenecyclobutane compounds (3-7) containing trifluoroborate:

[0100]

[0101] Compound 2-1 (0.1 mmol, 30 mg, 1.0 eq) and potassium hydrofluoric acid (1.0 mmol, 78 mg, 10.0 eq) were added to a 5 mL vial in a methanol-water solution (2:1 v / v). The mixture was stirred at room temperature for 13 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-7 in 71% yield. 1 H NMR (400MHz, CDCl3) δ6.15(d,J=8.4Hz,2H),5.83(d,J=8.4Hz,2H),3.91(s,1H),2.70( s,3H),2.28(p,J=8.0Hz,1H),2.06–1.96(m,1H),1.92–1.80(m,1H),1.64–1.32(m,2H).

[0102] Example 2.8: Synthesis of methylenecyclobutane compounds (3-8):

[0103]

[0104] Compound 2-1 (0.1 mmol, 30 mg, 1.0 eq), copper acetate (0.15 mmol, 30 mg, 1.5 eq), and water (1.0 mmol, 18 mg, 10.0 eq) were added to a 5 mL vial in acetonitrile. The mixture was stirred at 80 °C for 10 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-8 in 74% yield. 1 H NMR (400MHz, CDCl3) δ7.20(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),4.83(s,2H),3.80(s,3H),3.48(p,J=S35 8.4Hz,1H),3.15–3.02(m,2H),2.86–2.77(m,2H).

[0105] Example 2.9: Synthesis of methylene cyclobutane compounds (3-9) containing deuterium functional groups:

[0106]

[0107] Compound 2-1 (0.1 mmol, 30 mg, 1.0 eq), copper acetate (0.10 mmol, 20 mg, 1.0 eq), and deuterium water (1.0 mmol, 20 mg, 10.0 eq) were added to a 5 mL vial in acetonitrile. The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-9 in 60% yield. 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),5.00–4.70(m,1H),3.51(q,J=8.4Hz,1H),3.23–3.03(m,2H),2.90–2.73(m,2H).

[0108] Example 2.10: Synthesis of 2-(3-(4-methoxyphenyl)cyclobutyl)methyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane compound (3-10):

[0109]

[0110] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq) and 10% palladium on carbon (0.04 mmol, 4.2 mg, 0.2 eq) were added to a 5 mL vial in 1.0 mL tetrahydrofuran. The mixture was stirred under bubbling hydrogen gas at room temperature for 24 hours. After the reaction was complete, the product was separated by rotary evaporation under reduced pressure to obtain product 3-10 by silica gel column chromatography, yielding 85% product. 1 H NMR(400MHz, CDCl3)δ7 7.16(d,8.4Hz,0.6H),7.13(d,8.4Hz,1.4H),6.88–6.80(m,2H),3.79(s,0.9H),3. 78(s,2.1H),3.62–3.51(m,0.3H),3.29–3.17(m,0.7H),2.58–2.46(m,1.7H),2.45 –2.35(m,0.7H),2.34–2.25(m,0.6H),2.11–1.99(m,0.6H),1.76–1.64(m,1.4H),1 .243 (s, 3.6H), 1.240 (s, 8.4H), 1.14 (d, J = 8.0Hz, 0.6H), 0.97 (d, J = 7.6Hz, 1.4H).

[0111] Example 2.11: Synthesis of 3-(4-methoxyphenyl)cyclobutane-1-one compound (3-11):

[0112]

[0113] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq) was added to a 5 mL vial in 1.0 mL dichloromethane. Ozone was bubbled into the solution, and the mixture was stirred at -78°C for 3 hours. After the reaction was complete, a quencher (e.g., triphenylphosphine) was added. To separate the product, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-11 in 74% yield. 1 H NMR (400MHz, CDCl3) δ7.15 (d, J = 8.4Hz, 2H), 6.82 (d, J = 8.8Hz, 2H), 3.74 (s, 3H), 3.57 (p, J = 7.6Hz, 1H), 3.46–3.34 (m, 2H), 3.19–3.07 (m, 2H).

[0114] Example 2.12: Synthesis of methyl 4-(3-(4-methoxyphenyl)cyclobutylmethyl)benzoate compound (3-12):

[0115]

[0116] Compound 2-1 (0.2 mmol, 60 mg, 1.0 eq), methyl p-iodobenzoate (1.0 mmol, 262 mg, 5.0 eq), tetrakis(triphenylphosphine)palladium (0.04 mmol, 46 mg, 0.2 eq), and potassium carbonate (2.0 mmol, 276 mg, 10.0 eq) were added to a 5 mL vial of tetrahydrofuran in water (9:1 v / v). The mixture was stirred at 100 °C for 20 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-12 in 70% yield. 1 H NMR (400MHz, CDCl3) δ77.97(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),6.88(d,J=8.8Hz,2H),6.36–6.15(m,1 H), 3.90 (s, 3H), 3.80 (s, 3H), 3.66 (p, J = 8.0Hz, 1H), 3.54–3.40 (m, 1H), 3.35–3.24 (m, 1H), 3.24–3.11 (m, 1H), 3.09–2.97 (m, 1H).

[0117] Example 2.13: Synthesis of methylenecyclobutane derivative (3-13):

[0118]

[0119] Compound 2-3 (0.3 mmol, 58 mg, 1.0 eq), aryl halide S2 (1.2 mmol, 314 mg, 4.0 eq), tetraphenylphosphine palladium (0.06 mmol, 69 mg, 0.2 eq), and potassium carbonate (1.5 mmol, 207 mg, 5.0 eq) were added to a 5 mL vial in 3.0 mL of tetrahydrofuran aqueous solution (4:1 v / v). The mixture was stirred at 100 °C for 20 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-13 in 90% yield. 1H NMR (400MHz, CDCl3) δ8.13–7.91(m,2H),7.33–7.24(m,3H),7.26–7.15(m,2H),7.05(d ,J=8.4Hz,1H),4.03(s,0.4H),3.96(s,0.6H),3.93(s,1.2H),3.92(s,1.8H),3.68–3. 55(m,0.6H),3.24(p,J=8.8Hz,0.4H),3.13–3.03(m,0.6H),2.98–2.84(m,1H),2.80–2 .69(m,0.4H),2.63–2.50(m,1H),2.43–2.29(m,0.4H),2.08(dt,J=13.6,3.2Hz,0.6H).

[0120] Example 2.14: Synthesis of cyclobutane derivatives (3-15) with epoxy functional groups:

[0121]

[0122] Compound 3-14 (0.2 mmol, 62 mg, 1.0 eq), m-chloroperoxybenzoic acid (0.4 mmol, 69 mg, 2.0 eq), and sodium bicarbonate (0.2 mmol, 50 mg, 3.0 eq) were added to a 5 mL vial in 2.0 mL of dichloromethane. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-15 in 90% yield. 1 H NMR (400MHz, CDCl3) δ8.13–7.91(m,2H),7.33–7.24(m,3H),7.26–7.15(m,2H),7.05(d ,J=8.4Hz,1H),4.03(s,0.4H),3.96(s,0.6H),3.93(s,1.2H),3.92(s,1.8H),3.68–3. 55(m,0.6H),3.24(p,J=8.8Hz,0.4H),3.13–3.03(m,0.6H),2.98–2.84(m,1H),2.80–2 .69(m,0.4H),2.63–2.50(m,1H),2.43–2.29(m,0.4H),2.08(dt,J=13.6,3.2Hz,0.6H).

[0123] Example 2.15: Synthesis of cyclobutane derivatives (3-16) with epoxy functional groups:

[0124]

[0125] Compound 2-2 (0.2 mmol, 62 mg, 1.0 eq), p-toluenesulfonyl chloride (1.0 mmol, 190 mg, 5.0 eq), tetrakis(triphenylphosphine)palladium (0.02 mmol, 23 mg, 0.1 eq), and sodium carbonate (1.0 mmol, 83 mg, 5.0 eq) were added to a 5 mL vial in 3.0 mL of tert-butanol-water solution (1:1 v / v). The mixture was stirred at room temperature. After the reaction was complete, to separate the product, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-16 in 80% yield. 1 H NMR (400MHz, CDCl3) δ7.28S31(d,J=8.4Hz,4H),7.20(d,J=8.0Hz,4H),5.82(s,2H),3.54(q,J=8.4Hz,2H),3.30–3.08(m,4H),2.92–2.70(m,4H).

[0126] Example 2.16: Synthesis of cyclobutane derivatives (3-17) with epoxy functional groups:

[0127]

[0128] Compound 3-4' (0.2 mmol, 40 mg, 1.0 eq), methyltriphenylphosphine bromide (0.4 mmol, 143 mg, 2.0 eq), n-butyllithium (2.5 M in hexane, 0.4 mmol, 0.16 mL, 2.0 eq), and 2.0 mL of tetrahydrofuran were added to a 5 mL vial, and the mixture was stirred at -78 °C for 10 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-17 in 60% yield. 1H NMR(400MHz, CDCl3)δ4.84(s,0.33H),4.80(s,0.67H),4.62(s,0.33H),4.56(s,0.67H),4.30–4. 21(m,0.33H),4.19–4.09(m,0.33H),4.08–4.00(m,0.67H),3.99–3.86(m,0.67H),2.58(t,J=8.8 Hz,0.33H),2.39(t,J=9.2Hz,0.67H),2.23–2.10(m,1H),2.07–1.94(m,3.33H),1.93–1.84(m,0. 67H),1.68–1.54(m,4.33H),1.25(s,0.66H),1.19(s,2H),1.10(s,1H),0.96(s,1H),0.81(s,2H).

[0129] Example 2.17: Synthesis of dimethylmethylenecyclobutane derivatives (3-19) with hydroxyl functional groups:

[0130]

[0131] Compound 3-17 (0.2 mmol, 39 mg, 1.0 eq), sodium hydroxide (1.2 mmol, 48 mg, 6.0 eq), and 2.5 mL of methanol-water solution (4:1 v / v) were added to a 5 mL vial. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain product 3-18.

[0132] Example 2.18: Synthesis of dimethylmethylenecyclobutane derivatives (3-19) with hydroxyl functional groups:

[0133]

[0134] Compound 3-17' (0.2 mmol, 39 mg, 1.0 eq), sodium hydroxide (1.0 mmol, 40 mg, 5.0 eq), and 2.0 mL of methanol-water solution (1:1 v / v) were added to a 5 mL vial. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, to separate the product, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-19 in 74% yield. 1H NMR(400MHz, CDCl3)δ5.66(s,1H),4.29–3.96(m,2H),2.65–2.53(m,1H),2.26– 2.10(m,5H),1.88(s,3H),1.57(s,3H),1.45(s,3H),1.25(s,3H),1.14(s,3H).

[0135] Example 2.19: Synthesis of dimethylmethylenecyclobutane derivatives (3-20) with ester functional groups:

[0136]

[0137] Compound 15-1 (0.1 mmol, 15 mg, 1.0 eq), pyridine (0.5 mmol, 39 mg, 5.0 eq), DMAP (0.1 mmol, 12 mg, 1.0 eq), and the corresponding acylation reagent 3-methylcrotonyl chloride (0.15 mmol, 18 mg, 1.5 eq) were added to a 5 mL vial in 1.0 mL dichloromethane. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-20 in 68% yield. 1 HNMR(400MHz, CDCl3)δ5.66(s,1H),4.29–3.96(m,2H),2.65–2.53(m,1H),2.26 –2.10(m,5H),1.88(s,3H),1.57(s,3H),1.45(s,3H),1.25(s,3H),1.14(s,3H).

[0138] Example 15.2: Synthesis of a dimethylmethylenecyclobutane derivative (3-21) with a hydroxyl functional group:

[0139]

[0140] Compound 3-18 (0.1 mmol, 15 mg, 1.0 eq), pyridine (1.0 mmol, 78 mg, 10.0 eq), DMAP (0.2 mmol, 24 mg, 2.0 eq), and the corresponding acylation reagent 3,3-dimethylacryloyl chloride (0.15 mmol, 23 mg, 2.0 eq) were added to a 5 mL vial in dichloromethane. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, to separate the products, the volatile substances were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give product 3-21 in 65% yield. 1H NMR(400MHz, CDCl3)δ4.90(s,1H),4.85–4.80(m,2H),4.63(s,0.3H),4.56(s,0.7H),4.27(dd,J=11.2,8.0 Hz, 0.3H), 4.18 (dd, J=11.2, 7.2Hz, 0.3H), 4.07 (dd, J=11.2, 6.4Hz, 0.7H), 3.96 (dd, J=11.2, 8.8Hz, 0.7H), 3.03(s,0.6H),3.01(s,1.4H),2.59(t,J=8.8Hz,0.3H),2.44–2.33(m,0.7H),2.24–2.08(m,1H),1.93–1.8 4(m,1H),1.81(s,3H),1.65(s,3H),1.63–1.58(m,1H),1.19(s,2H),1.10(s,1H),0.96(s,1H),0.81(s,2H).

[0141] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions to the present invention without departing from the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing methylenecyclobutane derivatives having borate ester functional groups, characterized in that: Using compound 1 as a raw material, under the protection of inert argon gas, a catalyst and additives are added and reacted in a solvent to generate the target product; The reaction route is shown in equation (1) below: Wherein, R1, R2, R3 and R4 are hydrogen, an aliphatic hydrocarbon group with no more than 18 carbon atoms or an aromatic hydrocarbon group with no more than 18 carbon atoms, respectively; the LG group is a leaving group; the catalyst is a copper salt; the additives are pinacol diboronic acid ester and a base; the reaction time is 12 to 24 hours.

2. The method for synthesizing the methylenecyclobutane derivative according to claim 1, characterized in that: The alkali is any one of sodium methoxide, lithium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, and potassium tert-pentoxide.

3. The method for synthesizing the methylenecyclobutane derivative according to claim 1, characterized in that: The molar ratio of compound 1 to copper salt, pinacol diboronic acid ester, and base is 1:(0.05-0.20):(1.0-2.0):(0.20-2.0).

4. The method for synthesizing the methylenecyclobutane derivative according to claim 1, characterized in that: The solvent is any one of tetrahydrofuran (THF), benzene, toluene, DMF, DMA, and DCM.

5. A method for synthesizing methylenecyclobutane derivatives having other functional groups, characterized in that: Compound 2 was prepared by the method of synthesizing the methylene cyclobutane derivative according to any one of claims 1-4. Using compound 2 as a raw material, the target product was generated by adding additives in a solvent under the protection of inert argon gas. The reaction route is shown in equation (2) below: Wherein, R1, R2, R3, R4 and R5 are hydrogen, aliphatic hydrocarbon group with no more than 18 carbon atoms, aromatic hydrocarbon group or heteroatom group with no more than 18 carbon atoms, respectively; Bpin is pinacol borate ester; the additive is any one or a combination of several of the following: metal catalyst, base, oxidant, acylation reagent, olefination reagent, alkyne compound and aryl halide; the reaction time is 3-24 hours.

6. The synthesis method according to claim 5, characterized in that: The metal catalyst is a copper or palladium catalyst; the base is any one or a combination of several of sodium azide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium perborate hydrate, potassium carbonate, potassium hydrofluoric acid, potassium iodide, p-toluenesulfonyl chloride, sodium ascorbate, methyltriphenylphosphine bromide, n-butyllithium, and pyridine; the oxidant is m-chloroperoxybenzoic acid, hydrogen peroxide, or a combination thereof; the acylation reagent is a hydrocarbon carboxylic acid, acyl chloride, or acid anhydride compound with no more than 10 carbon atoms; the olefination reagent is a phosphonoacylacetic acid trialkyl ester with no more than 10 carbon atoms; the alkyne compound is an alkyne compound with various functional groups and no more than 20 carbon atoms; the aryl halide is an aromatic compound containing bromine, chlorine, or iodine, or a combination thereof, with no more than 20 carbon atoms.

7. The synthesis method according to claim 5, characterized in that: The molar ratio of compound 2 to the additive is 1:(0.05~10.0).

8. The synthesis method according to claim 5, characterized in that: The solvent is any one or a combination of several of the following: tetrahydrofuran (THF), benzene, toluene, DMF, DMA, DCM, acetonitrile, water, deuterated methanol, tert-butanol, and ammonia.

Images