A method for preparing an electrocatalytic scf-substituted dihydrofuran compound
Using diazo and ethylene compounds as substrates, SCF-substituted dihydrofuran compounds were synthesized via electrocatalysis, solving the problems of complex and environmentally unfriendly synthesis methods in existing technologies, and achieving a highly efficient and simple synthesis of dihydrofuran compounds.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JINING UNIV
- Filing Date
- 2026-04-15
- Publication Date
- 2026-06-05
AI Technical Summary
In the existing technology, the synthesis methods of SCF-substituted dihydrofuran have problems such as many substrate preparation steps, complex systems, and narrow condition control windows. In addition, traditional methods rely on photocatalytic systems or excessive redox reagents and lack green chemistry characteristics.
An electrocatalytic method is used to achieve a one-pot series reaction of cyclization through electrolysis using diazo and ethylene compounds as substrates. The current is used as the driving force of the reaction, combined with electrolyte and solvent, to form SCF-substituted dihydrofuran compounds, avoiding the use of additional photosensitizers and chemical redox reagents.
It realizes a one-pot series reaction of multiple steps, improves the efficiency of the steps, has readily available substrates, a wide range of applications, has the potential for further scale-up applications, and conforms to the characteristics of green chemistry, avoiding heavy metal residues.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of compound preparation technology, and in particular to a method for preparing an electrocatalytically SCF-substituted dihydrofuran compound. Background Technology
[0002] Dihydrofuran skeletons are an important class of oxygen-containing five-membered heterocyclic structures, widely found in natural products, drug molecules, and functional materials. Due to their structural characteristics, which allow for further functionalization and modification, and their high synthetic application value, efficient methods for constructing dihydrofuran skeletons have always been an important direction in organic synthesis research. Previous studies have shown that diazo and vinyl compounds can undergo cycloaddition reactions under appropriate conditions, thus providing a simple and efficient route for the construction of 2,3-dihydrofuran skeletons.
[0003] On the other hand, fluorinated sulfur functional groups such as SCF3 have attracted widespread attention in the fields of medicinal chemistry and fluorinated fine chemicals due to their strong electron-withdrawing properties, high lipophilicity, and ability to improve molecular metabolic stability and membrane permeability. Introducing SCF groups into heterocyclic skeletons, especially skeletons with further transformation potential such as dihydrofuran, can significantly enrich the fluorinated molecular library and enhance the application value of molecules.
[0004] In existing technologies, the synthetic methods for SCF-substituted dihydrofurans remain relatively limited. Some methods rely on pre-functionalized substrates, high temperatures, photocatalytic systems, or excess redox reagents, resulting in numerous substrate preparation steps, complex systems, and narrow control windows. In contrast, electroorganic synthesis uses electrons as clean redox reagents, offering advantages such as tunable conditions, universal equipment, ease of scale-up, and significant green chemistry characteristics. Especially for reactions involving free radical processes and metal-mediated coupling processes, electrochemical methods can achieve more precise control over the reaction pathway by adjusting current, potential, electrode materials, and charge. Summary of the Invention
[0005] Based on the above, the present invention aims to provide an electrocatalytic method for preparing SCF-substituted dihydrofuran compounds. This invention uses diazo and ethylene compounds as substrates and SCF as a sulfur- and fluorine-containing fragment donor, achieving a one-pot cascade reaction for cyclization via electrolysis to construct SCF-substituted dihydrofuran compounds. This method combines the advantages of readily available substrates, economical steps, and electrochemical control at the methodological level, possessing significant research value and potential application prospects.
[0006] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing an electrocatalytically SCF-substituted dihydrofuran compound includes the following steps: In the presence of an electrolyte and a solvent, compounds 1, 2 and 3 undergo an electrochemical reaction to yield target compound 4; The structural formula of compound 1 is as follows: R 1 Selected from alkyl, alkoxy, aryl, heterocyclic, or fused ring compounds; The structural formula of compound 2 is as follows: R 2 Selected from alkyl, alkenyl, aryl, heterocyclic, or fused ring compounds; Compound 3 is a trifluoromethylthio-based reagent capable of releasing SCF3 groups or forming active SCF3 species in situ with copper salts under electrochemical conditions; The structural formula of compound 4 is as follows: R 1 With R in compound 1 1 Consistent, R 2 With R in compound 2 2 Consistent.
[0007] Compared with traditional trifluoromethane sulfidation / cyclization methods that rely on photocatalytic systems, external strong oxidants, or high temperature conditions, the beneficial effects of this invention are mainly reflected in the following aspects: (1) Using current as the driving force for reaction avoids or reduces the use of additional photosensitizers and chemical redox reagents, making the system simpler and more prominent in green chemistry.
[0008] (2) The reaction has the characteristics of multiple steps such as CN bond breaking, CO bond construction, trifluoromethane sulfidation and cyclization in one pot, which can improve the efficiency of the steps.
[0009] (3) The substrate is mainly diazo, which is easy to prepare, and the raw materials are widely available.
[0010] (4) This method has good applicability to aryl and heteroaryl substituted substrates and has the basis for further scale-up applications.
[0011] The above-mentioned technical effects are due to the synergistic effect of the following key technical points: First, the electrolysis process can realize the single-electron oxidation of SCF source or promote the in-situ generation of metal-SCF active species on the anode side, thereby forming the active intermediate required for subsequent CS bond construction; Second, the combination of mass transfer at the electrode interface and homogeneous catalysis process enables bond breaking, capture and cyclization to be completed continuously in the same system. Detailed Implementation
[0012] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.
[0013] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.
[0014] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.
[0015] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.
[0016] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.
[0017] This invention provides a method for preparing an electrocatalytically SCF-substituted dihydrofuran compound, comprising the following steps: In the presence of an electrolyte and a solvent, compounds 1, 2 and 3 undergo an electrochemical reaction to yield target compound 4; The structural formula of compound 1 is as follows: R 1 Selected from alkyl, alkoxy, aryl, heterocyclic, or fused ring compounds; The structural formula of compound 2 is as follows: R 2 Selected from alkyl, alkenyl, aryl, heterocyclic, or fused ring compounds; Compound 3 is a trifluoromethylthio-based reagent capable of releasing SCF3 groups or forming active SCF3 species in situ with copper salts under electrochemical conditions; The structural formula of compound 4 is as follows: R 1 With R in compound 1 1 Consistent, R 2 With R in compound 2 2 Consistent.
[0018] The general reaction formula is: .
[0019] In a preferred embodiment of the present invention, the R 1 Selected from C1-C3 alkyl, C1-C3 alkoxy, phenyl, or thiophene group; R 2 It is selected from C1-C3 alkyl, vinyl, propenyl, biphenyl, substituted or unsubstituted phenyl, wherein substitution refers to substitution by Br, F, Cl or I.
[0020] In a preferred embodiment of the present invention, compound 3 is AgSCF3.
[0021] In a preferred embodiment of the present invention, the electrolyte is ammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate, or tetra-n-butylammonium perchlorate.
[0022] In a preferred embodiment of the present invention, the solvent is at least one of methanol, acetonitrile, tetrahydrofuran, dichloromethane, N,N-dimethylamide, dimethyl sulfoxide, and water.
[0023] More preferably, the solvent is a mixture of N,N-dimethylamide and water in a volume ratio of 4:1.
[0024] In a preferred embodiment of the present invention, the molar ratio of compound 1, compound 2, and compound 3 is 1:1:1 to 1:3:3; and the molar ratio of compound 1 to electrolyte is 1:1 to 1:3.
[0025] More preferably, the molar ratio of compound 1, compound 2, and compound 3 is 1:1.2:1.5; and the molar ratio of compound 1 to electrolyte is 1:1.
[0026] In a preferred embodiment of the present invention, the electrolysis mode during the electrochemical reaction is a constant current mode, a constant potential mode, a step electrolysis mode, or a pulse electrolysis mode.
[0027] In a preferred embodiment of the present invention, when the electrolysis mode is constant current mode, the current during the electrochemical reaction is 5-15 mA and the reaction time is 1-6 h.
[0028] More preferably, when the electrolysis mode is constant current mode, the current during the electrochemical reaction is 8mA and the reaction time is 4h.
[0029] In a preferred embodiment of the present invention, during the electrochemical reaction, the positive electrode material is selected from graphite rods, graphite felts, carbon cloth, glassy carbon, or platinum sheets; the negative electrode material is selected from platinum sheets, stainless steel sheets, nickel sheets, nickel foam, or graphite sheets.
[0030] The reaction intensity of the present invention can be finely controlled by constant current, constant potential, charge quantity and electrode material, which facilitates condition optimization for different substrates.
[0031] In a preferred embodiment of the present invention, after the electrochemical reaction is completed, the process further includes extracting and collecting the organic layer, and then sequentially drying, concentrating, and purifying the organic layer by silica gel column chromatography.
[0032] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.
[0033] To better understand the present invention, the following embodiments further illustrate the content of the present invention, but the content of the present invention is not limited to the following embodiments.
[0034] Example 1 In a 25 mL electrochemical reaction cell, reactants 1a (0.5 mmol, 1.0 equiv.), 2a (0.6 mmol, 1.2 equiv.), 3 (0.75 mmol, 1.5 equiv.), and tetrabutylammonium iodide (0.5 mmol, 1.0 equiv.) were added sequentially. N , N Dimethylamide (8 mL), water (2 mL), and a magnetic electrode were used. The electrolytic cell was equipped with a graphite rod anode (30 mm × 15 mm × 3 mm) as the anode and a Pt sheet (35 mm × 15 mm × 0.5 mm) as the cathode. The above mixture was electrolyzed at a constant current (8 mA) for 4 h at room temperature. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Afterwards, 40 mL of ethyl acetate and 20 mL of water were added for extraction and separation. The organic layers were combined, dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (V... 石油醚 :V 乙酸乙酯 The reaction ratio was 20:1, yielding compound SCF-substituted dihydrofuran 4a in 87% yield. The reaction equation is as follows: Colorless, viscous, oily liquid; yield 87% (140.1 mg); 1 H NMR (400 MHz, CDCl3) δ 7.77(dd, J = 6.7, 3.0 Hz, 2H), 7.31 – 7.23 (m, 8H), 7.24 – 7.17 (m, 1H), 5.60 (dd, J= 10.6, 8.7 Hz, 1H), 3.41 (dd, J = 15.1, 10.7 Hz, 1H), 2.96 (dd, J = 15.1, 8.7Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 162.5, 141.8, 130.4, 130.0 (q, J = 312.1 Hz),129.4, 129.0, 128.5, 128.5, 128.4, 125.9, 90.2 (q, J = 1.9 Hz), 82.2, 45.1; 19 FNMR (376 MHz, CDCl3) δ -42.4; HRMS (ESI) m / z [M + H] + calcd for C 17 H 14 F3OS323.0717, found 323.0714. Example 2 In a 25 mL electrochemical reaction cell, reactants 1b (0.5 mmol, 1.0 equiv.), 2a (0.6 mmol, 1.2 equiv.), 3 (0.75 mmol, 1.5 equiv.), and tetrabutylammonium iodide (0.5 mmol, 1.0 equiv.) were added sequentially. N , N Dimethylamide (8 mL), water (2 mL), and a magnetic electrode were used. The electrolytic cell was equipped with a graphite rod anode (30 mm × 15 mm × 3 mm) as the anode and a Pt sheet (35 mm × 15 mm × 0.5 mm) as the cathode. The above mixture was electrolyzed at a constant current (8 mA) for 4 h at room temperature. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Afterwards, 40 mL of ethyl acetate and 20 mL of water were added for extraction and separation. The organic layers were combined, dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (V...). 石油醚 :V 乙酸乙酯 The reaction ratio was 20:1, yielding compound SCF-substituted dihydrofuran 4b in 76% yield. The reaction equation is as follows: Colorless, viscous, oily liquid; yield 76% (124.6 mg); 1H NMR (400 MHz, CDCl3) δ 7.88 –7.83 (m, 2H), 7.42 – 7.37 (m, 3H), 7.31 (dd, J = 5.1, 1.2 Hz, 1H), 7.12 (dt, J =3.8, 1.1 Hz, 1H), 7.00 (dd, J = 5.1, 3.5 Hz, 1H), 5.95 (dd, J = 10.4, 8.5 Hz, 1H), 3.56 (dd, J = 15.1, 10.3 Hz, 1H), 3.22 (dd, J = 15.1, 7.7 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 161.9, 144.1, 130.2, 129.0, 128.4, 128.1, 127.2 (q, J =312.0 Hz), 127.1, 125.9, 125.4, 90.1 (q, J = 2.1 Hz), 77.9, 44.8; 19 F NMR (376MHz, CDCl3) δ -42.4; HRMS (ESI) m / z [M + H] + calcd for C 15 H 12 F3OS2329.0282, found329.0280. Example 3 In a 25 mL electrochemical reaction cell, reactants 1a (0.5 mmol, 1.0 equiv.), 2b (0.6 mmol, 1.2 equiv.), 3 (0.75 mmol, 1.5 equiv.), and tetrabutylammonium iodide (0.5 mmol, 1.0 equiv.) were added sequentially. N , NDimethylamide (8 mL), water (2 mL), and a magnetic electrode were used. The electrolytic cell was equipped with a graphite rod anode (30 mm × 15 mm × 3 mm) as the anode and a Pt sheet (35 mm × 15 mm × 0.5 mm) as the cathode. The above mixture was electrolyzed at a constant current (8 mA) for 4 h at room temperature. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Afterwards, 40 mL of ethyl acetate and 20 mL of water were added for extraction and separation. The organic layers were combined, dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (V... 石油醚 :V 乙酸乙酯 The ratio of the dihydrofuran compound to the saturated dihydrofuran compound was 20:1, yielding compound 4c, which was SCF-substituted, in 71% yield. The reaction equation is as follows: White solid; yield 71% (141.3 mg); 1 H NMR (400 MHz, CDCl3) δ 8.07 – 8.02 (m,2H), 7.71 – 7.60 (m, 4H), 7.51 – 7.46 (m, 2H), 7.46 – 7.41 (m, 4H), 7.41 –7.34 (m, 2H), 5.78 (dd, J = 10.7, 8.6 Hz, 1H), 3.59 (dd, J = 15.1, 10.7 Hz, 1H),3.14 (dd, J = 15.1, 8.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 162.1, 143.1, 141.8,140.5, 129.9 (q, J = 311.7 Hz), 129.1, 129.1, 128.9, 128.6, 128.2, 128.1,127.4, 127.1, 126.0, 90.2 (q, J = 2.1 Hz), 82.2, 45.3; 19 F NMR (376 MHz, CDCl3) δ-42.3; HRMS (ESI) m / z [M + H] + calcd for C 23 H 18 F3O S 399.1030, found 399.1035. Example 4 In a 25 mL electrochemical reaction cell, reactants 1a (0.5 mmol, 1.0 equiv.), 2c (0.6 mmol, 1.2 equiv.), 3 (0.75 mmol, 1.5 equiv.), and tetrabutylammonium iodide (0.5 mmol, 1.0 equiv.) were added sequentially. N , N Dimethylamide (8 mL), water (2 mL), and a magnetic electrode were used. The electrolytic cell was equipped with a graphite rod anode (30 mm × 15 mm × 3 mm) as the anode and a Pt sheet (35 mm × 15 mm × 0.5 mm) as the cathode. The above mixture was electrolyzed at a constant current (8 mA) for 4 h at room temperature. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Afterwards, 40 mL of ethyl acetate and 20 mL of water were added for extraction and separation. The organic layers were combined, dried over anhydrous Na₂SO₄, concentrated, and purified by silica gel column chromatography (V... 石油醚 :V 乙酸乙酯 The reaction ratio was 20:1, yielding compound SCF-substituted dihydrofuran 4d in 77% yield. The reaction equation is as follows: Colorless, viscous, oily liquid; yield 77% (153.61 mg); 1 H NMR (400 MHz, CDCl3) δ 7.86 –7.83 (m, 1H), 7.82 – 7.81 (m, 1H), 7.58 – 7.56 (m, 1H), 7.54 – 7.52 (m, 1H),7.43 – 7.32 (m, 5H), 5.73 (dd, J = 10.7, 8.7 Hz, 1H), 3.52 (dd, J = 15.2, 10.7Hz, 1H), 3.09 (dd, J = 15.2, 8.7 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 161.4,141.3, 131.5, 129.8, 129.8 (q, J = 315.15 Hz), 129.1, 128.7, 128.2, 125.9,124.8, 90.8 (q, J = 2.1 Hz), 82.1, 45.0; 19 F NMR (376 MHz, CDCl3) δ -42.4; HRMS(ESI) m / z [M + H] +calcd for C 17 H 13 F3BrO S 400.9823, found 400.9821. Comparative Example 1 The existing method for preparing SCF-substituted dihydrofuran compounds involves adding cyclopropyl ketone (0.2 mmol, 1.0 equiv.), AgSCF3 (0.3 mmol, 1.5 equiv.), and Ph-Mes-Acr to a 20 mL dry reaction tube under argon atmosphere. + BF4 - (0.01 mmol, 5 mol%), Cu(acac-F6)2 (0.02 mmol, 10 mol%), and Fe(OTf)3 (0.01 mmol, 5 mol%). The reaction tube was first evacuated, then purged with argon (3 times), and a stopper was placed above the tube. Next, 0.067 M acetonitrile solvent (3.0 mL) was added through the stopper using a syringe, and the reaction tube was placed approximately 5 cm from the light source. After 24 hours of reaction, 10 mL of ethyl acetate was added to the mixture, and the mixture was then passed through a silica gel chromatography column. Hexane and ethyl acetate were then used as eluents (V... 正己烷 :V 乙酸乙酯 The crude product was purified by rapid column chromatography with a ratio of 9.5:0.5 to obtain SCF3-substituted dihydrofuran in 70% yield (2).
[0035] Comparison of Comparative Example 1 and Examples 1-4 shows that the present invention has higher electrochemical driving efficiency, increasing the substrate conversion rate to 95%; avoids heavy metal residues, meeting the requirements of drug intermediates; eliminates the need for temperature control energy consumption, simplifies the process, improves efficiency, and has better functional group tolerance.
[0036] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing an electrocatalytically SCF-substituted dihydrofuran compound, characterized in that, Includes the following steps: In the presence of an electrolyte and a solvent, compounds 1, 2 and 3 undergo an electrochemical reaction to yield target compound 4; The structural formula of compound 1 is as follows: R 1 Selected from alkyl, alkoxy, aryl, heterocyclic, or fused ring compounds; The structural formula of compound 2 is as follows: R 2 Selected from alkyl, alkenyl, aryl, heterocyclic, or fused ring compounds; Compound 3 is a trifluoromethylthio-based reagent capable of releasing SCF3 groups or forming active SCF3 species in situ with copper salts under electrochemical conditions; The structural formula of compound 4 is as follows: R 1 With R in compound 1 1 Consistent, R 2 With R in compound 2 2 Consistent.
2. The preparation method according to claim 1, characterized in that, The R 1 Selected from C1-C3 alkyl, C1-C3 alkoxy, phenyl, or thiophene group; R 2 It is selected from C1-C3 alkyl, vinyl, propenyl, biphenyl, substituted or unsubstituted phenyl, wherein substitution refers to substitution by Br, F, Cl or I.
3. The preparation method according to claim 1, characterized in that, Compound 3 is AgSCF3.
4. The preparation method according to claim 1, characterized in that, The electrolyte is ammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate, or tetra-n-butylammonium perchlorate.
5. The preparation method according to claim 1, characterized in that, The solvent is at least one of methanol, acetonitrile, tetrahydrofuran, dichloromethane, N,N-dimethylamide, dimethyl sulfoxide, and water.
6. The preparation method according to claim 1, characterized in that, The molar ratio of compound 1, compound 2, and compound 3 is 1:1:1 to 1:3:3; the molar ratio of compound 1 to electrolyte is 1:1 to 1:
3.
7. The preparation method according to claim 1, characterized in that, During electrochemical reactions, the electrolysis mode can be constant current mode, constant potential mode, step electrolysis mode, or pulse electrolysis mode.
8. The preparation method according to claim 7, characterized in that, When the electrolysis mode is constant current mode, the current for the electrochemical reaction is 5-15 mA and the reaction time is 1-6 h.
9. The preparation method according to claim 1, characterized in that, During the electrochemical reaction, the positive electrode material is selected from graphite rods, graphite felts, carbon cloth, glassy carbon, or platinum sheets; the negative electrode material is selected from platinum sheets, stainless steel sheets, nickel sheets, nickel foam, or graphite sheets.
10. The preparation method according to claim 1, characterized in that, After the electrochemical reaction is completed, the process also includes extracting and collecting the organic layer, and then sequentially drying, concentrating, and purifying the organic layer by silica gel column chromatography.