Method for synthesizing bridged ring derivative through [4 +2] cycloaddition based on electrochemical means
By using electrochemical methods to carry out the [4+2] cycloaddition reaction, and utilizing anethole and cyclopentadiene derivatives to generate free radical cationic intermediates in an electrolytic cell, the problems of metal residue and environmental unfriendliness in existing technologies are solved, and green and efficient bridged ring derivative synthesis is achieved.
Patent Information
- Application Number
- CN202511770107.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-28
- Publication Date
- 2026-02-10
AI Technical Summary
Existing [4+2] cycloaddition reactions rely on thermal activation, photochemical or transition metal catalysts, which have problems such as the use of stoichiometric oxidants, metal residues and environmental unfriendliness.
An electrochemical method was employed, using anethole derivatives and cyclopentadiene derivatives as raw materials, tetrabutylammonium hexafluorophosphate or tetrabutylammonium perchlorate as electrolytes, and acetonitrile as solvent. Electrolysis was carried out in an electrolytic cell, and a cycloaddition reaction was carried out by generating free radical cationic intermediates using a constant current density.
It enables green synthesis without metal catalysts and with stoichiometric oxidants, with strong atom economy, mild reaction conditions, applicability to complex molecular synthesis, good stereoselectivity, and expands the scope of synthetic applications.
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Figure CN121496415A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing bridged ring derivatives based on electrochemical means [4+2] cycloaddition. Background Technology
[0002] The Diels–Alder (DA)[4+2] cycloaddition reaction is a landmark method in organic synthesis for constructing six-membered carbon ring skeletons and precisely introducing stereocenters. Its core mechanism involves the formation of two new C–C bonds between a conjugated diene and a dienophile through a coordinated and synchronous pericyclic process. It boasts significant advantages such as high atom economy and controllable regioselectivity and stereoselectivity. Since its discovery, this reaction has rapidly become a key tool in the total synthesis of natural products, the construction of core skeletons for drug molecules, materials chemistry, and pesticide development due to its concise and efficient cyclization characteristics. It is particularly suitable for the rapid assembly of complex molecules containing multi-substituted cyclohexenes, bridged rings, or heterocyclic structures.
[0003] Building upon the classic DA reaction, modern research continues to expand its application boundaries through catalytic system innovation and reaction condition optimization: Lewis acid catalysis can significantly reduce the reaction energy barrier and improve selectivity, while asymmetric catalysis strategies provide efficient pathways for chiral drug synthesis, and solvent effects, temperature control, and substrate modification further enhance the reaction's compatibility and practicality. This reaction can not only achieve precise construction of carbon-carbon bonds but also efficiently construct bridged ring derivatives (Tomoya Hisada, Kazumichi Maeda, Yasuhiro Yamashita,*and Shu Kobayashi*. Triarylmethyl Cationsas Photocatalysts for Radical-Mediated CycloadditionReactions[J]. Org. Lett. 2025, 27, 4366-4371).
[0004] As one of the most representative pericyclic reactions in organic synthesis, the mechanism and application of the DA[4+2] cycloaddition reaction have always been a hot topic in the field. Its concerted reaction characteristics avoid the generation of free radicals or ionic intermediates, reduce side reactions, and demonstrate its advantages under the concepts of green chemistry and efficient synthesis. Currently, this reaction has been widely used in the synthesis of everything from simple small molecules to complex natural products (such as terpenes and alkaloids), providing solid support for drug development, materials innovation, and advancements in organic synthesis methodologies, and continuously driving technological breakthroughs and industrial development in related fields.
[0005] However, existing synthetic methods often rely on thermal activation, photochemical processes, or transition metal catalysts, which have problems such as the use of stoichiometric oxidants, metal residues, poor compatibility of functional groups, and environmental unfriendliness. Summary of the Invention
[0006] The purpose of this invention is to provide a method for synthesizing bridged ring derivatives based on electrochemical means [4+2] cycloaddition.
[0007] The implementation process of this invention is as follows:
[0008] A method for synthesizing bridged ring derivatives by electrochemical means [4+2] cycloaddition includes the following steps: using anethole derivative 1 and cyclopentadiene derivative 2 as raw materials, using tetrabutylammonium hexafluorophosphate or tetrabutylammonium perchlorate as electrolyte, using acetonitrile solution as solvent, electrolyzing in an electrolytic cell at a constant current density, and obtaining bridged ring derivative 3 after purification;
[0009]
[0010] Wherein, R1 is selected from hydrogen-based, alkyl, halogen-based, and methyl ester-based groups with 1-6 carbon atoms; R2 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; R3 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; R4 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; R5 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; and R6 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms.
[0011] Furthermore, the molar ratio of the anethole derivative 1 to the cyclopentadiene derivative 2 is 1:5.
[0012] Furthermore, the constant current density is 20 mA / cm². 2 .
[0013] Furthermore, the molar ratio of the anethole derivative 1 to the electrolyte is 1:0.2.
[0014] Furthermore, the molar volume ratio of the electrolyte to the acetonitrile solution is 0.2 mmol: 30 mL.
[0015] Furthermore, the electrolysis time is 1.5 to 2 hours.
[0016] Furthermore, in the electrolytic cell, both the anode and cathode electrodes are carbon rod electrodes.
[0017] Furthermore, the purification process includes removing the acetonitrile solvent by vacuum distillation after electrolysis, and eluting the resulting residue by silica gel column chromatography.
[0018] Furthermore, the eluent for the silica gel column chromatography is a mixed solution of petroleum ether and ethyl acetate.
[0019] The positive effects of this invention:
[0020] (1) The method of the present invention does not require metal catalysts, stoichiometric oxidants or reducing agents, which conforms to the principles of green chemistry and reduces the environmental burden.
[0021] (2) This invention emphasizes its atom economy and sustainability. The reaction conditions are mild, the reaction time is short, the yield is 51%-81%, the stereoselectivity is good, it is suitable for the synthesis of complex molecules, and it is suitable for a variety of dienes and olefin derivatives. It has strong tolerance to functional groups, such as halogens and alkyl groups, thus expanding the scope of synthetic applications.
[0022] (3) This invention utilizes constant current electrolysis under metal-free and oxidant-free conditions to generate free radical cation intermediates through anodic oxidation, thereby achieving cycloaddition reaction. Attached Figure Description
[0023] Figure 1 The target product 3a prepared in Example 1 1 HNMR spectrum;
[0024] Figure 2 The target product 3a prepared in Example 1 13 C10 NMR spectrum;
[0025] Figure 3 This is a reaction mechanism diagram of a method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition. Detailed Implementation
[0026] The present invention will be further described below with reference to the embodiments.
[0027] Example 1
[0028]
[0029] At room temperature, an acetonitrile solution (30 mL) of compound 1b (1.0 mmol), compound 2d (5.0 mmol), and tetrabutylammonium hexafluorophosphate (TBAPF6, 0.2 mmol) was placed in an unseparated electrolytic cell. Two carbon rod electrodes were used as the anode and cathode electrodes, and an acetonitrile flow rate of 20 mA / cm² was applied. 2 Electrolysis was performed at a constant current density for 2 hours. After electrolysis, acetonitrile was removed by vacuum distillation, and the residue was purified by silica gel column chromatography, eluting with petroleum ether-ethyl acetate (volume ratio 10:1) to finally obtain 165.4 mg of the target product 3a, with a yield of 52%. The target product 3a... 1 The HNMR spectrum is shown below. Figure 1 , 13 The C NMR spectrum is shown below. Figure 2 .
[0030] 1H NMR (CDCl3, 400MHz) δ = 7.84 (d, J = 8.1Hz, 2H, Ar-H), 7.21 (dd, J = 14.2, 8.4Hz, 4H, Ar-H), 6 .83(d,J=8.7Hz,2H,Ar-H),6.45(dd,J=5.5,3.2Hz,1H,Ar-H),5.87(dd,J=5.6,2.8Hz,1H, CH),3.87-3.81(m,1H,CH),3.79(s,3H,CH),3.40(d,J=4.4Hz,1H,CH),3.32(s,1H,CH),3. 05(s,1H,CH),2.40(s,3H,CH),2.01(d,J=8.5Hz,1H,CH),1.63(dd,J=8.5,1.4Hz,1H,CH). 13 C NMR (CDCl3, 100MHz) δ = 199.8, 57.9, 143.6, 139.3, 137.0, 133.1, 129.4, 128.7, 128.6, 114.1, 56.3, 55.5, 49.0, 48.8, 48.1, 45.3, 21.8ppm. HRMS (ESI, positive ions):m / z=319.1678(calcd for[3a+H] + =319.1693).
[0031] Comparative Example 1
[0032] In Example 1, the carbon rod electrode at the anode was replaced with a platinum electrode (Pt electrode), while other experimental conditions remained unchanged. The final product 3a was 10.1 mg, with a yield of 3.1%.
[0033] Comparative Example 2
[0034] By replacing the carbon rod electrode of the cathode in Example 1 with a platinum electrode (Pt electrode) while keeping other experimental conditions unchanged, the target product 3a was finally obtained in 53 mg, with a yield of 16.7%.
[0035] Comparative Example 3
[0036] The constant current density in Example 1 was reduced to 10 mA / cm². 2 With other experimental conditions unchanged, the target product 3a was finally obtained in a dose of 46.4 mg, with a yield of 14.5%.
[0037] Comparative Example 4
[0038] The constant current density in Example 1 was reduced to 5 mA / cm². 2 With other experimental conditions unchanged, the target product 3a was finally obtained in a dose of 38.2 mg, with a yield of 11.9%.
[0039] Comparative Example 5
[0040] The constant current density in Example 1 was reduced to 0 mA / cm². 2 With other experimental conditions unchanged, the target product 3a was not generated.
[0041] Comparative Example 6
[0042] In Example 1, the electrolyte tetrabutylammonium hexafluorophosphate was replaced with tetrabutylammonium bromide (TBAB), and other experimental conditions remained unchanged. The target product 3a was not generated.
[0043] Comparative Example 7
[0044] In Example 1, the electrolyte tetrabutylammonium hexafluorophosphate was replaced with tetrabutylammonium iodide (TBAI), and other experimental conditions remained unchanged. The target product 3a was not generated.
[0045] Comparative Example 8
[0046] In Example 1, the electrolyte tetrabutylammonium hexafluorophosphate was replaced with tetrabutylammonium chloride (TBAC), while other experimental conditions remained unchanged. The final product 3a was 4 mg, with a yield of 1.2%.
[0047] Comparative Example 9
[0048] In Example 1, the electrolyte tetrabutylammonium hexafluorophosphate was replaced with tetrabutylammonium perchlorate (TBAClO4), while other experimental conditions remained unchanged. The final product 3a was 162.1 mg, with a yield of 51%.
[0049] Examples 1 and Comparative Examples 1-2 demonstrate that using carbon rod electrodes for both the anode and cathode facilitates the addition reaction and results in a higher yield of the target product. Examples 1 and Comparative Examples 3-5 show that the constant current density is reduced to 20 mA / cm². 2 The addition reaction is more easily promoted, resulting in a higher yield of the target product. Examples 1 and Comparative Examples 6-9 demonstrate that using tetrabutylammonium hexafluorophosphate and tetrabutylammonium perchlorate as electrolytes more easily promotes the addition reaction and results in a higher yield of the target product.
[0050] Therefore, the optimal conditions were determined to be: using tetrabutylammonium hexafluorophosphate (TBAPF6) or tetrabutylammonium perchlorate (TBAClO4) as the electrolyte, and a current density of 20 mA / cm². 2 Carbon rod electrodes were used as both the anode and cathode, with acetonitrile as the solvent, and the reaction was carried out at room temperature. Optimization studies showed that halide-based electrolytes performed poorly, while hexafluorophosphate and perchlorate electrolytes achieved high yields. Controlled experiments confirmed that electrocatalysis was crucial; no reaction occurred without current.
[0051] Example 2
[0052]
[0053] An acetonitrile solution (30 mL) of compound 1a (1.0 mmol), compound 2e (5.0 mmol), and tetrabutylammonium hexafluorophosphate (TBAPF6, 0.2 mmol) was placed in an unseparated electrolytic cell. Two carbon rod electrodes were used as the anode and cathode electrodes, and an acetonitrile flow rate of 20 mA / cm² was applied. 2 Electrolysis was performed at a constant current density for 2 hours. After electrolysis, acetonitrile was removed by vacuum distillation, and the residue was purified by silica gel column chromatography by elution with petroleum ether-ethyl acetate (volume ratio 5:1) to finally obtain the target product 3b266.4 mg, with a yield of 74%.
[0054] 1 H NMR (CDCl3, 400MHz) δ = 7.83-7.76 (m, 2H, Ar-H), 7.48 (t, J = 7.4, 7.4Hz, 1H, Ar-H), 7.37 (t, J=7.6,7.6Hz,2H,Ar-H),7.22(d,J=8.6Hz,2H,Ar-H),6.84(d,J=8.7Hz,2H),4.02(d,J=5.6 Hz,1H,CH),3.79(s,3H,CH),3.07(d,J=4.3Hz,1H,CH),2.00(d,J=8.4Hz,1H,CH),1.72(s, 3H,CH),1.47(s,3H,CH),1.24(dd,J=8.4,1.6Hz,1H,CH),1.19(s,3H,CH),0.77(s,3H,CH). 13 C NMR (CDCl3, 100MHz) δ = 202.0, 158.2, 141.7, 139.4, 136.9, 134.9, 132.6, 129.7, 128.5, 128. 4,113.7,62.6,58.5,56.4,55.4,54.9,54.4,18.3,15.5,11.7,9.6ppm.HRMS(ESI,positive ions):m / z=361.2254(calcd for[3b+H] + =361.2162).
[0055] Example 3
[0056]
[0057] An acetonitrile solution (30 mL) of compound 1b (1.0 mmol), compound 2e (5.0 mmol), and tetrabutylammonium hexafluorophosphate (TBAPF6, 0.2 mmol) was placed in an unseparated electrolytic cell. Two carbon rod electrodes were used as the anode and cathode electrodes, and an acetonitrile flow rate of 20 mA / cm² was applied. 2 Electrolysis was performed at a constant current density for 2 hours. After electrolysis, acetonitrile was removed by vacuum distillation, and the residue was purified by silica gel column chromatography by elution with petroleum ether-ethyl acetate (volume ratio 8:1) to finally obtain the target product 3c284.4mg, with a yield of 76%.
[0058] 1 H NMR (CDCl3, 400MHz) δ = 7.71 (d, J = 8.2Hz, 2H, Ar-H), 7.21 (d, J = 8.7Hz, 2H, Ar-H), 7.17 (d, J = 8 .0Hz,2H,Ar-H),6.83(dd,J=8.8,2.4Hz,2H,Ar-H),4.00(d,J=5.6Hz,1H,CH),3.79(d,J=2.7H z,3H,CH),3.07(d,J=5.4Hz,1H,CH),2.36(s,3H,CH),1.99(d,J=8.4Hz,1H,CH),1.72(s,3H,C H),1.46(s,3H,CH),1.23(ddd,J=70.5,8.4,1.7Hz,1H,CH),1.19(s,3H,CH),0.77(s,3H,CH). 13 C NMR(CDCl3,100MHz)δ=201.5,158.2,143.3,141.6,137.0,136.9,135.1,129.7,129.2,128.6, 113.7,62.4,58.5,56.3,55.4,54.9,54.4,21.7,18.3,15.5,11.7,9.6ppm.HRMS(ESI,positive ions):m / z=375.2429(calcdfor[3c+H] + =375.2319).
[0059] Example 4
[0060]
[0061] An acetonitrile solution (30 mL) of compound 1a (1.0 mmol), compound 2f (5.0 mmol), and tetrabutylammonium hexafluorophosphate (TBAPF6, 0.2 mmol) was placed in an unseparated electrolytic cell. Two carbon rod electrodes were used as the anode and cathode electrodes, and an acetonitrile flow rate of 20 mA / cm² was applied.2 Electrolysis was performed at a constant current density for 1.5 hours. After electrolysis, acetonitrile was removed by vacuum distillation, and the residue was purified by silica gel column chromatography by elution with petroleum ether-ethyl acetate (volume ratio 10:1) to finally obtain the target product 3e3O3 3.1 mg, with a yield of 81%.
[0062] 1 H NMR (CDCl3, 400MHz) δ = 7.79 (d, J = 7.8Hz, 2H, Ar-H), 7.48 (t, J = 7.3, 7.3Hz, 1H, Ar-H), 7.3 7(t,J=7.7,7.7Hz,2H,Ar-H),7.22(d,J=8.6Hz,2H,Ar-H),6.82(d,J=8.6Hz,2H,Ar-H),3 .95(d,J=5.8Hz,1H,CH),3.78(s,3H,CH),3.07(d,J=5.7Hz,1H,CH),2.12(q,J=6.4,6.3, 6.3Hz,1H,CH),1.66(s,3H,CH),1.42(s,3H,CH),1.05(s,3H,CH),0.68-0.60(m,6H,CH). 13 C NMR(CDCl3,100MHz)δ=202.1,158.1,139.7,137.6,134.7,132.7,132.5,130.0,128.4,128.4, 113.6,62.3,59.5,58.9,57.9,55.3,54.0,16.0,13.3,11.9,9.9,8.4ppm.HRMS(ESI,positive ions):m / z=375.2305(calcd for[3e+H] + =375.2319).
[0063] Example 5
[0064]
[0065] An acetonitrile solution (30 mL) of compound 1b (1.0 mmol), compound 2f (5.0 mmol), and tetrabutylammonium perchlorate (TBAClO4, 0.2 mmol) was placed in an unseparated electrolytic cell. Two carbon rod electrodes were used as the anode and cathode electrodes, and an acetonitrile flow rate of 20 mA / cm² was applied. 2 Electrolysis was performed at a constant current density for 2 hours. After electrolysis, acetonitrile was removed by vacuum distillation, and the residue was purified by silica gel column chromatography by elution with petroleum ether-ethyl acetate (volume ratio 5:1) to finally obtain the target product 3f318.4 mg, with a yield of 82%.
[0066] 1 H NMR (CDCl3, 400MHz) δ = 7.71 (d, J = 8.2Hz, 2H, Ar-H), 7.22 (d, J = 8.7Hz, 2H, Ar-H), 7.1 7(d,J=8.3Hz,2H,Ar-H),6.82(d,J=8.7Hz,2H,Ar-H),3.93(d,J=5.7Hz,1H,CH),3.78 (s,3H,CH),3.07(d,J=5.7Hz,1H,CH),2.36(s,3H,CH),2.12(q,J=6.4,6.4,6.4Hz,1H ,CH),1.66(s,3H,CH),1.44-1.39(m,3H,CH),1.06(s,3H,CH),0.68-0.58(m,6H,CH). 13 C NMR(CDCl3,100MHz)δ=201.5,158.1,143.2,137.4,137.1,134.9,132.8,130.0,129.2,128.6,11 3.6,62.1,59.4,58.8,57.9,55.4,54.0,21.7,16.0,13.4,12.0,9.9,8.5ppm.HRMS(ESI,positive ions):m / z=389.2473(calcd for[3f+H] + =389.2475).
[0067] Examples 6-10: In the method for synthesizing bridged ring derivatives based on electrochemical means [4+2] cycloaddition according to the present invention, there are multiple choices for anethole derivative 1 and cyclopentadiene derivative 2. Some examples are shown in the table below.
[0068]
[0069]
[0070] The reaction mechanism of the method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to the present invention is as follows: Figure 3 As shown: Starting with the oxidation of electron-rich olefin A (anesinol derivative 1) at the anode to generate the key electrophilic free radical cation intermediate B, in the [4+2] cycloaddition reaction, intermediate B cross-couples with conjugated diene derivative C (cyclopentadiene derivative 2) to form bridged ring free radical cation D, and then bridged ring free radical cation D is reduced to generate the final bridged ring derivative 3.
[0071] Antibacterial performance test:
[0072] (1) 10 mg of the bridged ring derivatives prepared in Examples 1, 6 and 7 were dissolved in 0.1 mL of DMSO solution, and then diluted with 20 mL of distilled water to obtain Sample 1, Sample 2 and Sample 3.
[0073] (2) Take 20 μl of Pseudomonas aeruginosa suspension and spread it evenly on an agar plate using a spreader. There are 6 agar plates with the Pseudomonas aeruginosa suspension. Use tweezers sterilized with an alcohol lamp to pick up 6 mm diameter filter paper discs and place them on each agar plate, dividing them into three groups. Transfer 1-3 drops of 100 μl sample to the corresponding group of filter paper discs. After the sample has completely penetrated, incubate in a constant temperature incubator at 37℃ for 10 h. Remove the culture medium and measure the diameter of the inhibition zone.
[0074] The measurement results are shown in the table below. It can be seen from the table that the bridged ring derivatives prepared in Examples 1, 6 and 7 have antibacterial effects against Pseudomonas aeruginosa.
[0075]
[0076]
[0077] Other embodiments of this application will readily conceive of by those skilled in the art upon consideration of the specification and practice of the disclosure herein. This application is intended to cover any variations, uses, or adaptations of this application that follow the general principles of this application and include common knowledge or customary techniques in the art not disclosed herein. The specification and embodiments are to be considered exemplary only, and this application is not limited to the precise structures described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope.
Claims
1. A method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition, characterized in that: Using anethole derivative 1 and cyclopentadiene derivative 2 as raw materials, tetrabutylammonium hexafluorophosphate or tetrabutylammonium perchlorate as electrolyte, and acetonitrile solution as solvent, electrolysis was carried out in an electrolytic cell at a constant current density, and bridged ring derivative 3 was obtained after purification. Wherein, R1 is selected from hydrogen-based, alkyl, halogen-based, and methyl ester-based groups with 1-6 carbon atoms; R2 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; R3 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; R4 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; R5 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms; and R6 is selected from hydrogen-based and alkyl groups with 1-6 carbon atoms.
2. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: The molar ratio of the anethole derivative 1 to the cyclopentadiene derivative 2 is 1:
5.
3. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: The constant current density is 20 mA / cm². 2 .
4. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: The molar ratio of the anethole derivative 1 to the electrolyte is 1:0.
2.
5. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: The molar volume ratio of the electrolyte to the acetonitrile solution is 0.2 mmol: 30 mL.
6. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: The electrolysis time is 1.5 to 2 hours.
7. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: In the electrolytic cell, both the anode and cathode electrodes are carbon rod electrodes.
8. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 1, characterized in that: The purification process includes removing acetonitrile solvent by vacuum distillation after electrolysis, and eluting the residue by silica gel column chromatography.
9. The method for synthesizing bridged ring derivatives based on electrochemical [4+2] cycloaddition according to claim 8, characterized in that: The eluent for the silica gel column chromatography is a mixed solution of petroleum ether and ethyl acetate.