Method for preparing remote oxyimidization product based on olefin 1, 5-HAT strategy, product and application

Abstract

The invention discloses a method for preparing a remote oxyimidization product based on an olefin 1, 5-HAT strategy, the product and application, and belongs to the technical field of organic synthesis.The method comprises the following steps that unactivated olefin containing a benzoyl skeleton, oxime carbonate, a catalyst and an organic solvent are mixed and then stirred to react under the illumination condition, the solvent is removed after the reaction is finished, and the remote oxyimidization product is obtained. And carrying out purification treatment to obtain the remote oxyimidization product. The method provided by the invention not only is simple and convenient to operate, but also is green and environment-friendly, and provides a novel and potential synthesis strategy for constructing a complex compound skeleton containing a C-N bond and a C-O bond and realizing a remote position bifunctionalization reaction.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method, product and application for preparing remote oxyiminated products based on the olefin 1,5-HAT strategy. Background Art

[0002] As one of the core strategies in modern organic synthetic chemistry, difunctionalization reactions have demonstrated significant advantages in the construction of complex molecular skeletons and the precise synthesis of multi-functional compounds. Their interdisciplinary application value has extended to the fields of drug development and functional material design. Difunctionalization reagents represented by benzophenone-derived oxime esters have achieved efficient transformation from simple olefins to complex functional molecules through the ability to simultaneously introduce two different functional groups. The high atom economy characteristics of such reagents perfectly meet the development needs of green synthetic chemistry. Under photo-driven conditions, the homolytic cleavage of the N-O bond in oxime ester reagents can generate imine nitrogen-centered radicals and oxygen-centered radicals, and the synergistic effect of the two provides a unique reaction path for the difunctionalization modification of unsaturated bonds.

[0003] In the field of remote difunctionalization, various transformation modes have been achieved based on the radical-mediated 1,5-hydrogen atom transfer (HAT) mechanism. However, for the specific type of olefin remote oxyimination, there is still room for optimization in terms of regioselectivity and reaction efficiency, and the development of new catalytic systems is urgently needed. The core challenge in current research lies in balancing reaction activity and selectivity. Through the regulation of the steric electronic effect of the substrate skeleton and the systematic optimization of reaction conditions, it is expected to break through the existing limitations and achieve efficient and precise control of olefin remote difunctionalization reactions.

[0004] Therefore, how to provide a method that can achieve the ideal effect of efficient remote difunctionalization of olefins is a technical problem that needs to be urgently solved by those skilled in the art. Summary of the Invention

[0005] To solve the above technical problems, the present invention proposes a method, product and application for preparing remote oxyiminated products based on the olefin 1,5-HAT strategy.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A method for preparing remote oxyiminated products based on the olefin 1,5-HAT strategy, comprising the following steps:

[0008] Mix an unactivated olefin containing a benzoyl skeleton, an oxime carbonate, a catalyst and an organic solvent, and stir the reaction under light conditions. After the reaction is completed, remove the solvent and perform purification treatment to obtain the remote oxyiminated product.

[0009] Beneficial effects: The present invention adopts a visible-light-catalyzed room-temperature reaction system, replaces traditional metal catalysts with low-cost organic photosensitizer TX, and realizes the precise oxyamination of remote sites of olefins through a two-component 1,5-HAT strategy. This design has three advantages: 1) Mild conditions (room temperature / visible light) meet the requirements of green chemistry; 2) Efficiently construct C-O, C-H, and C-N bonds in one step, with excellent atom economy; 3) The radical precursor / acceptor combination optimized based on the principle of polarity matching ensures excellent regioselectivity and chemoselectivity. The reaction principle of the preparation method in the present invention is as follows:

[0010]

[0011] Preferably, the molar ratio of the unactivated olefin containing a benzoyl skeleton to the oxime carbonate is 2:3.

[0012] Beneficial effects: A slight excess (1.5 equiv) of the oxime carbonate in the present invention ensures complete reaction, while suppressing the polyfunctionalization side reactions caused by excessive olefins, enabling the 1,5-HAT process to accurately and efficiently direct γ-site functionalization.

[0013] Preferably, the unactivated olefin containing a benzoyl group skeleton is selected from one or more of diethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate, dimethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate, diethyl 2-allyl-2-(3-oxo-3-(p-tolyl)propyl)malonate, diethyl 2-allyl-2-(3-(4-methoxyphenyl)-3-oxopropyl)malonate, diethyl 2-allyl-2-(3-(4-chlorophenyl)-3-oxopropyl)malonate, and diethyl 2-allyl-2-(3-(4-bromophenyl)-3-oxopropyl)malonate.

[0014] Beneficial effects: The inertness of unactivated olefins makes them difficult to react under traditional conditions. The present invention realizes efficient and selective conversion through a photocatalytic radical mechanism, and the specific spatial arrangement of the benzoyl group and the olefin ensures the efficient occurrence of the 1,5-HAT process.

[0015] Preferably, the oxime carbonate is benzophenone-O-propoxycarbonyl oxime and benzophenone-O-butoxycarbonyl oxime.

[0016] More preferably, the preparation method of benzophenone-O-propoxycarbonyl oxime comprises the following steps:

[0017] Benzophenone oxime (20 mmol, 1.0 equiv) and propyl chloroformate (22 mmol, 1.1 equiv) were placed in a 250 mL flask, and then pyridine (1.78 mL, 1.1 equiv) and dry dichloromethane solvent (80 mL, 0.25 M) were added and mixed evenly. Then, the mixture was placed under an air atmosphere at room temperature and reacted overnight for 12 h. The reaction was monitored by thin-layer chromatography (TLC), and the crude product was separated and purified by column chromatography to obtain the product benzophenone-O-propoxycarbonyl oxime.

[0018] More preferably, the method for preparing benzophenone-O-butoxycarbonyl oxime (2b) comprises the following steps:

[0019]

[0020] Benzophenone oxime (20 mmol, 1.0 equiv) and butyl chloroformate (22 mmol, 1.1 equiv) were placed in a 250 mL flask, and then pyridine (1.78 mL, 1.1 equiv) and dry dichloromethane solvent (80 mL, 0.25 M) were added and mixed evenly. Then, the mixture was placed under an air atmosphere at room temperature and reacted overnight for 12 h. After the reaction, the reaction was monitored by thin-layer chromatography (TLC), and the crude product was separated and purified by column chromatography to obtain the product benzophenone-O-propoxycarbonyl oxime.

[0021] Beneficial effects: The propoxycarbonyl or butoxycarbonyl in the above compounds acts as a protecting group, which can precisely modify the oxime hydroxyl group to form a special oxime ester structure. This structure can selectively homolyze the N-O bond under photocatalysis, simultaneously release oxygen / nitrogen free radicals to participate in the difunctionalization of olefins, and retain the subsequent transformation potential of propoxycarbonyl or butoxycarbonyl.

[0022] Preferably, the catalyst is thioxanthone (TX).

[0023] Beneficial effects: The present invention selects the low-cost organic photosensitizer TX as the catalyst, which has both high catalytic activity and environmental friendliness.

[0024] Preferably, the organic solvent is ethyl acetate.

[0025] Beneficial effects: Selecting ethyl acetate as the solvent in the present invention has multiple advantages: excellent solubility can stably dissolve key reactants such as benzoyl olefins and carbonic oxime esters; low toxicity (LD50 5600 mg / kg) meets the green chemistry standard; the moderate boiling point of 77 °C is convenient for vacuum recovery (recovery rate > 90%) and is compatible with silica gel column chromatography; its cost is only 1 / 3 of that of acetonitrile, combining environmental protection and economy.

[0026] A remote oxyiminated product prepared by a method for preparing a remote oxyiminated product based on the olefin 1,5-HAT strategy.

[0027] Preferably, the structural formula is as shown in formula (I):

[0028]

[0029] Wherein, R1 is -H, -Me, -Cl, -Br or -OCH3;

[0030] R2 is -Et or -Me;

[0031] R3 is -CH2CH2CH3 or -CH2CH2CH2CH3.

[0032] Beneficial effects: By flexibly adjusting the R1 and R3 substituents (such as halogens, alkyl groups, alkoxy groups, etc.), the present invention can directionally construct 1,6-remote oxyiminated products with diverse structures, significantly expanding the application scope of the products in molecular modification. The obtained nitrogen / oxygen heterocyclic skeletons (such as when R1 is a halogen) have characteristics similar to natural products and may have potential biological activities.

[0033] Use of a remote oxyiminated product in organic chemical transformation or synthesis of bioactive molecules.

[0034] Beneficial effects: By combining unactivated alkenes with benzoyl skeletons and carbonate oximes, the present invention can achieve a unique reaction mechanism of oxygen radical addition - 1,5-hydrogen atom transfer (HAT) - radical coupling, efficiently synthesizing long-chain products containing various easily transformable functional groups. This remote oxyiminated product shows unique potential in organic chemical transformation and synthesis of bioactive molecules. These products can be hydrolyzed to generate γ-amino acid derivatives, which have potential biological activities and can participate in reactions such as amidation and condensation as bioactive carriers to expand structural diversity. Their unique skeletons can also undergo intramolecular cyclization to generate lactone or lactam compounds, and these cyclic structures have important values in medicinal chemistry and can be used as precursors for antibiotics, anti-tumor drugs or neuroactive drugs. In addition, the C=N bond in the products can further participate in radical functionalization reactions. These characteristics make them have important application values in the fields of organic synthesis, drug research and development, chemical biology, etc.

[0035] Compared with the prior art, the present invention has the following advantages and technical effects:

[0036] The present invention utilizes the homolytic cleavage process of the N-O bond to generate stable nitrogen-centered imine radicals and transient oxygen-centered radicals under the action of visible light catalysis. Among them, the oxygen-centered radicals will accurately add to the terminal of the olefin to generate secondary carbon radicals. Subsequently, through a 1,5-hydrogen atom transfer (HAT) reaction, the radical will migrate to the α-position of the benzoyl group and undergo cross-coupling with the previously generated stable nitrogen-centered imine radical. This series of precise steps ultimately enables the efficient synthesis of 1,6-remote oxyimine products. The method provided by the present invention is not only simple to operate but also environmentally friendly, providing a novel and highly potential synthetic strategy for constructing complex compound skeletons containing C-N bonds and C-O bonds and realizing dual-functionalization reactions at remote positions. Detailed implementation manners

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0038] To make the above objects, features, and advantages of the present invention more obvious and understandable, the present invention will be further described in detail below in conjunction with specific implementation manners.

[0039] Unless otherwise specified, the raw materials in the embodiments of the present invention are all obtained through commercial channels.

[0040] Unless otherwise specified, the room temperature or normal temperature in the embodiments of the present invention refers to 25 ± 3°C.

[0041] Example 1

[0042] The synthesis of diethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate (1a) specifically includes the following steps:

[0043]

[0044] Dissolve diethyl allylmalonate (5 mmol) in THF (5 mL) and cool to 0°C, then add NaH (6.5 mmol) and react for 30 min; dissolve 3-chloropropiophenone (5 mmol) in THF (5 mL), slowly add it to the above reaction mixture, and finally add TBAI (0.5 mmol). After transferring the reaction system to room temperature, heat it to 66°C and reflux overnight for 12 h. Finally, monitor by TLC and separate and purify by column chromatography to obtain the product solution, and then rotary evaporate the solvent to obtain the product 1a with a yield of 67%; performance characterization: yellow solid.

[0045] Example 2

[0046] The synthesis of dimethyl 2 - allyl - 2-(3 - oxo - 3 - phenylpropyl)malonate (1b) specifically includes the following steps:

[0047]

[0048] Dissolve dimethyl allylmalonate (5 mmol) in THF (5 mL), cool it to 0 °C, add NaH (6.5 mmol) and react for 30 min; dissolve 3 - chloropropiophenone (5 mmol) in THF (5 mL), slowly add it to the above - mentioned mixed solution, and finally add TBAI (0.5 mmol). After the reaction is transferred to room temperature, heat it to 66 °C and reflux overnight for 12 h. Finally, monitor by TLC and separate and purify by column chromatography to obtain the product solution, then rotary - evaporate the solvent to obtain product 1b with a yield of 74%; performance characterization: yellow solid.

[0049] Example 3

[0050] The synthesis of diethyl 2 - allyl - 2-(3 - oxo - 3-(p - tolyl)propyl)malonate (1c) specifically includes the following steps:

[0051]

[0052] Dissolve diethyl allylmalonate (5 mmol) in THF (5 mL), cool it to 0 °C, add NaH (6.5 mmol) and react for 30 min. Dissolve 3 - chloro - 1-(p - tolyl)propan - 1 - one (5 mmol) in THF (5 mL), slowly add it to the above - mentioned mixed solution, and finally add TBAI (0.5 mmol). After the reaction is transferred to room temperature, heat it to 66 °C and reflux overnight for 12 h. Finally, monitor by TLC and separate and purify by column chromatography to obtain the product solution, then rotary - evaporate the solvent to obtain product 1c with a yield of 53%; performance characterization: yellow solid.

[0053] Example 4

[0054] The synthesis of diethyl 2 - allyl - 2-(3-(4 - bromophenyl)-3 - oxopropyl)malonate (1d) specifically includes the following steps:

[0055]

[0056] Dissolve diethyl allylmalonate (5 mmol) in THF (5 mL) and cool to 0 °C. Add NaH (6.5 mmol) and react for 30 min. Dissolve 1-(4-bromophenyl)-3-chloro-1-propanone (5 mmol) in THF (5 mL), slowly add it to the above mixture, and finally add TBAI (0.5 mmol). After the reaction is transferred to room temperature, heat it to 66 °C and reflux overnight for 12 h. Finally, monitor by TLC and separate and purify by column chromatography to obtain the product solution. Then rotary evaporate the solvent to obtain product 1d with a yield of 51%. Performance characterization: yellow solid.

[0057] Example 5

[0058] The synthesis of diethyl 2-allyl-2-(3-(4-chlorophenyl)-3-oxopropyl)malonate (1e) specifically includes the following steps:

[0059]

[0060] Dissolve diethyl allylmalonate (5 mmol) in THF (5 mL) and cool to 0 °C. Add NaH (6.5 mmol) and react for 30 min. Dissolve 3-chloro-1-(4-chlorophenyl)propan-1-one (5 mmol) in THF (5 mL), slowly add it to the above mixture, and finally add TBAI (0.5 mmol). After the reaction is transferred to room temperature, heat it to 66 °C and reflux overnight for 12 h. Finally, monitor by TLC and separate and purify by column chromatography to obtain the product solution. Then rotary evaporate the solvent to obtain product 1e with a yield of 58%. Performance characterization: yellow solid.

[0061] Example 6

[0062] The synthesis of diethyl 2-allyl-2-(3-(4-methoxyphenyl)-3-oxopropyl)malonate (1f) specifically includes the following steps:

[0063]

[0064] Dissolve diethyl allylmalonate (5 mmol) in THF (5 mL) and cool to 0 °C. Add NaH (6.5 mmol) and react for 30 min. Dissolve 3-chloro-1-(4-methoxyphenyl)propan-1-one (5 mmol) in THF (5 mL), slowly add it to the above mixture, and finally add TBAI (0.5 mmol). After the reaction is transferred to room temperature, heat it to 66 °C and reflux overnight for 12 h. Finally, monitor by TLC and separate and purify by column chromatography to obtain the product solution. Then rotary evaporate the solvent to obtain product 1f with a yield of 72%. Performance characterization: yellow solid.

[0065] Example 7

[0066] Synthesis of benzophenone - O - propoxycarbonyl oxime (2a) specifically includes the following steps:

[0067]

[0068] Place benzophenone oxime (20 mmol, 1.0 equiv) and propyl chloroformate (22 mmol, 1.1 equiv) in a 250 mL flask, then add pyridine (1.78 mL, 1.1 equiv) and dry dichloromethane solvent (80 mL, 0.25 M), mix well, and then place it in an air atmosphere at room temperature for overnight reaction for 12 h. Use thin - layer chromatography (TLC) to monitor the reaction and column chromatography to separate and purify the crude product to obtain product 2a with a yield of: 76%, and the property characterization: white solid.

[0069] Example 8

[0070] Synthesis of benzophenone - O - butoxycarbonyl oxime (2b) specifically includes the following steps:

[0071]

[0072] Place benzophenone oxime (20 mmol, 1.0 equiv) and butyl chloroformate (22 mmol, 1.1 equiv) in a 250 mL flask, then add pyridine (1.78 mL, 1.1 equiv) and dry dichloromethane solvent (80 mL, 0.25 M), mix well, and then place it in an air atmosphere at room temperature for overnight reaction for 12 h. After the reaction, use thin - layer chromatography (TLC) to monitor the reaction and column chromatography to separate and purify the crude product to obtain product 2b with a yield of: 73%, and the property characterization: white solid.

[0073] Example 9

[0074] Synthesis of diethyl 2 - (2 - ((diphenylmethylene)amino)-3 - oxo - 3 - phenylpropyl)-2-(3 - ((propoxycarbonyl)oxy)propyl)malonate (3a) specifically includes the following steps:

[0075]

[0076] 0.2 mmol of diethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate (product 1a obtained in Example 1), 0.3 mmol of benzophenone-O-propoxycarbonyl oxime (product 2a obtained in Example 7), 2 mL of ethyl acetate and 5 mol% (i.e., the amount of the catalyst is 5% of the total amount of 1a and 2a) of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stir bar. Then, the tube was purged with argon three times, the tube mouth was capped, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE-PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3a with a yield of 68%.

[0077] Product characterization:

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.73 - 7.71 (m, 2H), 7.65 - 7.63 (m, 2H), 7.49 - 7.46 (m, 1H), 7.38 - 7.35 (m, 5H), 7.34 - 7.28 (m, 3H), 7.05 - 7.03 (m, 2H), 4.86 (dd, J = 9.5, 3.4 Hz, 1H), 4.12 - 4.05 (m, 5H), 4.03 - 3.97 (m, 3H), 2.85 (dd, J = 14.6, 9.5 Hz, 1H), 2.54 (dd, J = 14.7, 3.4 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.92 - 1.85 (m, 1H), 1.68 - 1.61 (m, 2H), 1.43 - 1.37 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H) ppm;

[0079] 13 C NMR (125 MHz, CDCl3) δ 199.6, 171.01, 170.98, 170.5, 155.3, 138.9, 136.6, 135.7, 133.0, 130.6, 129.0, 128.8, 128.70, 128.65, 128.4, 128.1, 127.6, 67.8, 67.6, 65.9, 61.52, 61.50, 56.4, 36.4, 30.8, 29.1, 23.7, 19.0, 14.03, 14.00, 13.8 ppm;

[0080] HRMS (ESI): C 36H 41 NO8H + [M+H] + Calcd 616.2905,Found 616.2905.

[0081] Example 10

[0082] Synthesis of dimethyl 2-(2-((diphenylmethylene)amino)-3-oxo-3-phenylpropyl)-2-(3-((propoxycarbonyl)oxy)propyl)malonate (3b) specifically includes the following steps:

[0083]

[0084] 0.2 mmol of dimethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate (product 1b obtained in Example 2), 0.3 mmol of benzophenone-O-propoxycarbonyl oxime (product 2a obtained in Example 7), 2 mL of ethyl acetate and 5 mol% of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stirrer. Then, it was purged with argon three times, the seal of the tube mouth was screwed on, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction was completed, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE - PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3b with a yield of 32%.

[0085] Product characterization:

[0086] 1 H NMR(500MHz,CDCl3)δ7.69(d,J = 8.0Hz,2H),7.64(d,J = 7.9Hz,2H),7.48(t,J = 7.2Hz,1H),7.38 - 7.34(m,4H),7.33 - 7.29(m,4H),7.05 - 7.03(m,2H),4.89(dd,J = 9.4,3.5Hz,1H),4.07(t,J = 6.7Hz,2H),4.00(t,J = 6.3Hz,2H),3.62(s,3H),3.58(s,3H),2.82(dd,J = 14.6,9.3Hz,1H),2.55(dd,J = 14.6,3.6Hz,1H),2.01(td,J = 13.3,4.3Hz,1H),1.89(td,J = 13.3,4.3Hz,1H),1.69(q,J = 7.1Hz,2H),1.61 - 1.57(m,1H),1.48 - 1.40(m,1H),0.96(t,J = 7.4Hz,3H)ppm;

[0087] 13 13C NMR (125 MHz, CDCl3) δ 199.5, 171.4, 170.9, 155.3, 138.8, 136.5, 135.6, 133.0, 130.6, 128.9, 128.8, 128.7, 128.4, 128.1, 127.5, 69.6, 67.5, 65.5, 56.3, 52.7, 52.6, 36.6, 29.4, 23.7, 22.1, 10.3 ppm;

[0088] HRMS (ESI): C 34 H 37 NO8H + [M + H] + Calcd 588.2592, Found 588.2607.

[0089] Example 11

[0090] Synthesis of diethyl 3-(2-((diphenylmethylene)amino)-3-oxo-3-(p-tolyl)propyl)-2-(3-((propoxycarbonyl)oxy)propyl)malonate (3c) specifically includes the following steps:

[0091]

[0092] 0.2 mmol of diethyl 2-allyl-2-(3-oxo-3-(p-tolyl)propyl)malonate (product 1c obtained in Example 3), 0.3 mmol of benzophenone-O-propoxycarbonyl oxime (product 2a obtained in Example 7), 2 mL of ethyl acetate, and 5 mol% of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stir bar, then purged with argon three times, the tube mouth was capped, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction was completed, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE - PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3c with a yield of 68%.

[0093] Product characterization:

[0094] 11H NMR (500 MHz, CDCl3) δ 7.65 - 7.63 (m, 4H), 7.38 - 7.35 (m, 4H), 7.32 - 7.28 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 - 7.03 (m, 2H), 4.82 (dd, J = 9.6, 3.4 Hz, 1H), 4.13 - 4.06 (m, 5H), 4.02 - 3.98 (m, 3H), 2.84 (dd, J = 14.7, 9.6 Hz, 1H), 2.53 (dd, J = 14.7, 3.4 Hz, 1H), 2.35 (s, 3H), 2.00 (td, J = 13.9, 13.4, 4.5 Hz, 1H), 1.87 (td, J = 13.9, 13.3, 4.2 Hz, 1H), 1.66 - 1.61 (m, 2H), 1.42 - 1.38 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H) ppm;

[0095] 13 13C NMR (125 MHz, CDCl3) δ 199.2, 171.04, 170.99, 170.3, 155.3, 143.8, 139.0, 136.6, 133.0, 130.5, 129.2, 129.1, 128.8, 128.7, 128.6, 128.1, 127.6, 67.8, 67.6, 65.9, 61.5, 61.5, 56.4, 36.5, 30.8, 29.0, 23.8, 21.7, 19.0, 14.03, 14.00, 13.8 ppm;

[0096] HRMS (ESI): C 37 H 43 NO8H + [M + H] + Calcd 630.3061, Found 630.3054.

[0097] Example 12

[0098] The synthesis of diethyl 2-(2-((diphenylmethylene)amino)-3-(4-methoxyphenyl)-3-oxopropyl)-2-(3-((propoxycarbonyl)oxy)propyl)malonate (3d) specifically includes the following steps:

[0099]

[0100] 0.2 mmol of diethyl 2-allyl-2-(3-(4-methoxyphenyl)-3-oxopropyl)malonate (product 1d obtained in Example 4), 0.3 mmol of benzophenone-O-propoxycarbonyl oxime (product 2a obtained in Example 7), 2 mL of ethyl acetate and 5 mol% of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stir bar, followed by purging with argon three times. The sealed tube mouth was capped, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE-PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3d with a yield of 22%.

[0101] Product characterization:

[0102] 1 H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 7.3 Hz, 2H), 7.39 - 7.35 (m, 4H), 7.32 - 7.29 (m, 2H), 7.05 - 7.03 (m, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.79 (dd, J = 9.5, 3.4 Hz, 1H), 4.10 - 4.05 (m, 5H), 4.02 - 3.98 (m, 3H), 3.83 (s, 3H), 2.85 (dd, J = 14.7, 9.5 Hz, 1H), 2.54 (dd, J = 14.7, 3.4 Hz, 1H), 1.99 (td, J = 13.6, 4.4 Hz, 1H), 1.87 (td, J = 13.3, 4.1 Hz, 1H), 1.69 (q, J = 7.1 Hz, 2H), 1.64 - 1.60 (m, 1H), 1.50 - 1.42 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H) ppm;

[0103] 13 C NMR (125 MHz, CDCl3) δ 198.0, 171.1, 171.0, 170.2, 163.5, 155.4, 139.0, 136.6, 131.6, 130.6, 128.8, 128.7, 128.6, 128.4, 128.1, 127.7, 113.7, 69.6, 67.7, 66.1, 61.54, 61.52, 56.4, 55.6, 36.7, 29.1, 23.8, 22.2, 14.07, 14.05, 10.4 ppm;

[0104] HRMS(ESI): C 37 H 43 NO9H + [M + H] + Calcd 646.3011, Found 646.3010.

[0105] Example 13

[0106] Synthesis of diethyl 2-(3-(4-chlorophenyl)-2-((diphenylmethylene)amino)-3-oxopropyl)-2-(3-((propoxycarbonyl)oxy)propyl)malonate (3e) specifically includes the following steps:

[0107]

[0108] 0.2 mmol of diethyl 2-allyl-2-(3-(4-chlorophenyl)-3-oxopropyl)malonate (product 1e obtained in Example 5), 0.3 mmol of benzophenone - O - propoxycarbonyl oxime (product 2a obtained in Example 7), 2 mL of ethyl acetate, and 5 mol% of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stirrer. Then, it was purged with argon three times, the seal of the tube mouth was screwed on, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction was completed, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE - PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3e with a yield of 42%.

[0109] The product was characterized as:

[0110] 11H NMR (500 MHz, CDCl3) δ 7.75 - 7.74 (m, 2H), 7.63 - 7.61 (m, 2H), 7.39 - 7.36 (m, 4H), 7.34 - 7.29 (m, 4H), 7.02 (dd, J = 6.2, 2.9 Hz, 2H), 4.81 (dd, J = 9.4, 3.5 Hz, 1H), 4.11 - 4.06 (m, 6H), 4.03 - 3.98 (m, 2H), 2.81 (dd, J = 14.6, 9.4 Hz, 1H), 2.52 (dd, J = 14.6, 3.5 Hz, 1H), 1.98 (td, J = 13.4, 4.8 Hz, 1H), 1.87 (td, J = 13.4, 4.3 Hz, 1H), 1.71 - 1.67 (m, 2H), 1.65 - 1.59 (m, 1H), 1.49 - 1.42 (m, 1H), 1.19 (t, J = 7.3 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H) ppm;

[0111] 13 13C NMR (125 MHz, CDCl3) δ 198.3, 171.0, 170.9, 170.8, 155.3, 139.5, 138.8, 136.4, 133.8, 130.9, 130.7, 128.84, 128.80, 128.79, 128.7, 128.2, 128.1, 127.6, 69.6, 67.6, 66.1, 61.62, 61.60, 56.3, 36.5, 29.1, 23.7, 22.1, 14.1, 14.04, 14.01, 10.4 ppm;

[0112] HRMS (ESI): C 36 H 40 ClNO8H + [M + H] + Calcd 650.2515, Found 650.2513.

[0113] Example 14

[0114] Synthesis of diethyl 3-(3-(4-bromophenyl)-2-((diphenylmethylene)amino)-3-oxopropyl)-2-(3-((propoxycarbonyl)oxy)propyl)malonate (3f) specifically includes the following steps:

[0115]

[0116] 0.2 mmol of diethyl 2 - allyl - 2-(3-(4 - bromophenyl)-3 - oxopropyl)malonate (product 1f obtained in Example 6), 0.3 mmol of benzophenone - O - propoxycarbonyl oxime (product 2a obtained in Example 7), 2 mL of ethyl acetate and 5 mol% of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stir bar. Then, the tube was purged with argon three times, the tube mouth was capped, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction was completed, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE - PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3f with a yield of 48%.

[0117] Examples 1 - 8 are publicly reported olefins or radical precursor substrates with high chemical reactivity. The combination of such olefins or radical precursor substrates and oxamination oxime esters can achieve a complex reaction pathway of oxygen radical addition - 1,5 - HAT - radical coupling to synthesize the long - chain products containing propoxycarbonyl, ester, benzoyl, and imine groups in Examples 9 - 15. After hydrolysis, these long - chain products can obtain derivatives of γ - amino acids, which can further participate in various organic reactions as potential bioactive carriers, such as amidation reactions, condensation reactions, etc. Due to the special skeleton, intramolecular cyclization may directly occur to generate potentially bioactive lactones or lactams. The C=N bond in the skeleton may further participate in radical functionalization reactions as a receptor.

[0118] The product was characterized as follows:

[0119] 11H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.39 - 7.37 (m, 3H), 7.31 (t, J = 7.6 Hz, 2H), 7.03 - 7.01 (m, 2H), 4.81 (dd, J = 9.4, 3.5 Hz, 1H), 4.10 - 4.05 (m, 5H), 4.01 - 3.97 (m, 3H), 2.81 (dd, J = 14.6, 9.4 Hz, 1H), 2.52 (dd, J = 14.7, 3.6 Hz, 1H), 1.98 (td, J = 13.4, 4.7 Hz, 1H), 1.87 (td, J = 13.3, 4.2 Hz, 1H), 1.69 (q, J = 7.1 Hz, 2H), 1.67 - 1.59 (m, 1H), 1.49 - 1.41 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H) ppm;

[0120] 13 13C NMR (125 MHz, CDCl3) δ 198.5, 171.1 170.9, 170.8, 155.3, 138.8, 137.7, 136.4, 134.3, 132.6, 131.8, 130.80, 130.75, 130.2, 128.9, 128.8, 128.7, 128.4, 128.3, 128.2, 127.6, 69.6, 67.6, 66.2, 61.61, 61.59, 56.3, 36.5, 29.2, 23.8, 22.2, 14.1, 14.0, 10.4, 10.3 ppm;

[0121] HRMS (ESI): C 36 H 40 BrNO8H + [M + H] + Calcd 694.2010, Found 694.2018.

[0122] Example 15

[0123] Synthesis of diethyl 2-(3-((butoxycarbonyl)oxy)propyl)-2-(2-((diphenylmethylene)amino)-3-oxo-3-phenylpropyl)malonate (3 g) specifically includes the following steps:

[0124]

[0125] 0.2 mmol of diethyl 2 - allyl - 2-(3 - oxo - 3 - phenylpropyl)malonate (product 1a obtained in Example 1), 0.3 mmol of benzophenone - O - butoxycarbonyl oxime (product 2b obtained in Example 8), 2 mL of ethyl acetate and 5 mol% of catalyst TXT were successively added to a 15 mL sealed tube equipped with a magnetic stir bar. Then, the tube was purged with argon three times, the tube mouth was capped, and the reaction was stirred for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light was 3 cm away from the reaction vessel. After the reaction was completed, the solvent was removed under reduced pressure, and the reaction solution was purified by column chromatography (silica gel, PE - PE / EtOAc = 1:49 to 1:19). Finally, the purified product was rotary evaporated and dried to obtain product 3g with a yield of 45%.

[0126] The product was characterized as follows:

[0127] 1 H NMR (500 MHz, CDCl3) δ 7.73 - 7.71 (m, 2H), 7.65 - 7.63 (m, 2H), 7.49 - 7.46 (m, 1H), 7.38 - 7.36 (m, 4H), 7.34 - 7.29 (m, 4H), 7.05 - 7.03 (m, 2H), 4.86 (dd, J = 9.5, 3.4 Hz, 1H), 4.12 - 4.07 (m, 5H), 4.01 - 3.98 (m, 3H), 2.84 (dd, J = 14.7, 9.5 Hz, 1H), 2.54 (dd, J = 14.7, 3.4 Hz, 1H), 2.00 (td, J = 13.5, 4.5 Hz, 1H), 1.88 (td, J = 13.7, 13.3, 4.2 Hz, 1H), 1.67 - 1.61 (m, 4H), 1.42 - 1.38 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H) ppm;

[0128] 13 C NMR (125 MHz, CDCl3) δ 199.7, 171.1, 171.0, 170.6, 155.4, 139.0, 136.6, 135.7, 133.0, 130.6, 129.1, 128.8, 128.74, 128.70, 128.5, 128.1, 127.6, 67.9, 67.6, 65.9, 61.6, 56.4, 36.4, 30.8, 29.1, 23.8, 19.1, 14.1, 14.0, 13.8 ppm;

[0129] HRMS (ESI): C 37 H43 NO8H + [M+H] + Calculated 630.3061, Found 630.3054.

[0130] Example 16

[0131] Preparation method and product characterization of 2,6 - di - tert - butyl - 4 - ((diphenylmethyleneamino)methyl)phenol (4a), 3,5 - di - tert - butyl - 4 - hydroxybenzyl propyl carbonate (4b), diethyl 2 - (2 - (3,5 - di - tert - butyl - 4 - hydroxybenzyl)-3 - ((propoxycarbonyl)oxy)propyl)-2 - (3 - oxo - 3 - phenylpropyl)malonate (4c) or diethyl 2 - (2 - (3,5 - di - tert - butyl - 4 - hydroxybenzyl)-3 - oxo - 3 - phenylpropyl)-2 - (3 - (propoxycarbonyl)oxy)propyl)malonate (4d):

[0132]

[0133] Add 0.15 mmol of benzophenone - O - propoxycarbonyl oxime (product 2a obtained in Example 7), 0.1 mmol of diethyl 2 - allyl - 2 - (3 - oxo - 3 - phenylpropyl)malonate (product 1a obtained in Example 1), 2 mol% of TX and 1 mL of ethyl acetate into a 15 mL sealed tube equipped with a magnetic stir bar, then add 0.3 mmol of BHT (2,6 - di - tert - butyl - p - cresol), and then displace with argon three times. Screw the cap of the sealed tube and stir the reaction for 24 h under irradiation with a 30 w 395 nm LED light, where the LED light is 3 cm away from the reaction vessel. After the reaction, products 4a, 4b, 4c or 4d in the reaction mixture are monitored by high - resolution mass spectrometry.

[0134] The above 4a - 4d are key radical intermediates successfully captured by the radical trapping experiment. Combining with the previous literature reports and the trapping experiment results of the present invention, it further confirms the possible radical reaction mechanism of this remote oxy - imination reaction.

[0135] Product characterization is as follows:[[]]

[0136] 4a HRMS(ESI): C 28 H 33 NOH + [M + H] + Calculated 400.2635, Found 400.2631.

[0137] 4b HRMS(ESI): C 19 H 30 O4Na + [M + Na]+ Calculated 345.2036, Found 345.2045.

[0138] 4c or 4d HRMS(ESI): C 38 H 54 O9Na + [M + Na] + Calculated 677.3060, Found 677.3653.

[0139] The above are only the preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed in the present application should be covered by the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A method for preparing a remote oxyimine product based on the alkene 1,5-HAT strategy, characterized in that, It includes the following steps: Mix the unactivated olefin containing a benzoyl skeleton, the carbonate oxime ester, the catalyst and the organic solvent, and then stir and react under light conditions. After the reaction is completed, remove the solvent and obtain the target remote oxyiminated product through purification treatment.

2. The method for preparing a remote oxyimine product based on the alkene 1,5-HAT strategy according to claim 1, characterized in that, The addition ratio of the unactivated olefin containing a benzoyl skeleton to the carbonate oxime ester is 2:

3.

3. A method for preparing a remote oxime product based on the alkene 1,5-HAT strategy according to claim 1, characterized in that, The unactivated olefin containing a benzoyl skeleton is selected from one or more of diethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate, dimethyl 2-allyl-2-(3-oxo-3-phenylpropyl)malonate, diethyl 2-allyl-2-(3-oxo-3-(p-tolyl)propyl)malonate, diethyl 2-allyl-2-(3-(4-methoxyphenyl)-3-oxopropyl)malonate, diethyl 2-allyl-2-(3-(4-chlorophenyl)-3-oxopropyl)malonate and diethyl 2-allyl-2-(3-(4-bromophenyl)-3-oxopropyl)malonate.

4. A method for preparing a remote oxyimine product based on the alkene 1,5-HAT strategy according to claim 1, characterized in that, The carbonate oxime ester is benzophenone-O-propoxycarbonyl oxime and benzophenone-O-propoxycarbonyl oxime.

5. A method for preparing a remote oxime product based on the alkene 1,5-HAT strategy according to claim 1, characterized in that, The catalyst is thioxanthone.

6. The method for preparing a remote oxime product based on the alkene 1,5-HAT strategy according to claim 1, wherein The organic solvent is ethyl acetate.

7. The remote oxyiminated product prepared by the method for preparing a remote oxyiminated product based on the olefin 1,5-HAT strategy according to any one of claims 1-6.

8. The remote oxime imide product according to claim 7, characterized in that, The structural formula is shown in formula (I): Wherein, R1 is -H, -Me, -Cl, -Br or -OCH3; R2 is -Et or -Me; R3 is -CH2CH2CH3 or -CH2CH2CH2CH3.

9. The application of the remote oxyiminated product according to claim 7 or 8 in organic chemical transformation or the synthesis of bioactive molecules.

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