A method for synthesizing 2,5-disubstituted furans via CC double bond cleavage free radical tandem electrosynthesis

Abstract

The present invention discloses a method for synthesizing 2,5-disubstituted furans by series electrosynthesis of C-C double bond cleavage free radicals, wherein enaminone, an organic electrolyte and an acidic additive are dissolved in a solvent to obtain a homogeneous solution; the homogeneous solution is then added to an electrochemical reaction device, fully reacted, and the product is collected to obtain. Compared with the prior art, the synthesis process operation of the present invention has the advantages of low cost, green and efficient, safe and non-toxic, and mild reaction conditions. At the same time, the present invention does not need to add other catalysts and oxidants, overcomes the problems such as harsh reaction conditions in traditional systems, and high atomic and step-by-step product synthesis is achieved, which has a wide range of application prospects in the synthesis of pharmaceutical products.

Description

Technical Field

[0001] The present invention belongs to the fields of medicinal chemistry and fine chemical synthesis, and particularly relates to a method for tandem electrosynthesis of 2,5-disubstituted furans via C-C double bond cleavage free radicals. Background Art

[0002] Substituted furans are ubiquitous in natural products and have been widely used in medicinal chemistry, materials science, and the flavor and fragrance industry. Therefore, the development of practical, efficient, and green methods to construct structures including furan skeletons has received widespread attention. In this context, chemists have proposed several traditional methods, including the Feist-Bénary reaction. However, the synthesis of most furan compounds is limited by low yield and selectivity, the use of stoichiometric oxidants, and multiple pre-functionalization steps. In contrast, the electro-excited radical tandem cyclization strategy omits the pre-functionalization step of the starting materials, effectively simplifying the raw materials and shortening the reaction route. However, there are currently few reports on the electrochemical synthesis of 2,5-disubstituted furans. Summary of the Invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide a method for the tandem electrosynthesis of 2,5-disubstituted furans by C-C double bond cleavage free radicals, so as to solve the problems of low yield and selectivity, the use of stoichiometric oxidants and multi-step pre-functionalization in the existing technology.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0005] A method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals comprises the following steps:

[0006] (1) dissolving the enaminone represented by formula 1, an organic electrolyte, and an acidic additive in a solvent to obtain a homogeneous solution;

[0007] (2) adding the homogeneous solution in step (1) into an electrochemical reaction device, reacting sufficiently, and collecting the product shown in formula 2 to obtain;

[0008] The above reaction equation is:

[0009] ;

[0010] Among them, R 1 is an electron-donating group or an electron-withdrawing group; the electron-donating group is selected from any one of hydrogen, 1-4 C alkyl, methoxy or trifluoromethoxy; the electron-withdrawing group is selected from any one of halogen and trifluoromethyl.

[0011] Specifically, in step (1), the acidic additive is selected from one or a mixture of two or more of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, lithium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and nickel trifluoromethanesulfonate. Preferably, it is any one or a combination of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid; more preferably, it is p-toluenesulfonic acid.

[0012] Specifically, in step (1), the organic electrolyte is selected from one or a mixture of two or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroacetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroiodide, and tetrabutylammonium tetrafluoroperchlorate. Preferably, the organic electrolyte is any one or a combination of tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroacetate, tetrabutylammonium hexafluorophosphate, and tetrabutylammonium tetrafluoroiodide; more preferably, tetrabutylammonium hexafluorophosphate and tetrabutylammonium tetrafluoroborate; and even more preferably, tetrabutylammonium hexafluorophosphate.

[0013] Specifically, in step (1), the solvent is selected from one or a mixture of two or more of dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, N,N-dimethylaniline, tetrahydrofuran, water, methanol, and ethanol. Preferably, the solvent is any one or a combination of dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, N,N-dimethylaniline, and water; more preferably, trifluoroethanol, acetonitrile, hexafluoroisopropanol, and water; and even more preferably, a mixed solvent of acetonitrile and water.

[0014] Specifically, in step (1), the molar ratio of the enaminone, the acidic additive, and the organic electrolyte is (1-2): 2: 2. Preferably, it is 1-1.5: 2: 2; more preferably, it is 1-1.2: 2: 2; and even more preferably, it is 1: 2: 2.

[0015] Specifically, in step (1), the concentration of enaminone in the obtained homogeneous solution is 0.03-0.12 mmol / mL, preferably 0.03-0.10 mmol / mL, more preferably 0.03-0.05 mmol / mL, and even more preferably 0.0375 mmol / mL.

[0016] Specifically, in step (1), the concentration of the acidic additive in the obtained homogeneous solution is 0.03-0.12 mmol / mL.

[0017] Specifically, in step (1), the concentration of the organic electrolyte in the obtained homogeneous solution is 0.06-0.12 mmol / mL, preferably 0.06-0.10 mmol / mL, more preferably 0.06-0.08 mmol / mL, and even more preferably 0.075 mmol / mL.

[0018] Specifically, in step (2), the current intensity of the electrochemical reaction device is 8-20 mA, preferably 8-15 mA; further preferably 10 mA.

[0019] Specifically, in step (2), the reaction temperature is 20-80°C, preferably 20-50°C, and more preferably 25°C.

[0020] Specifically, in step (2), the reaction time is 90-150 min, preferably 90-120 min, and more preferably 90 min.

[0021] Furthermore, in step (2), after the reaction is completed, the reaction solution is extracted to obtain an organic phase, which is concentrated and subjected to column chromatography to obtain the product shown in Formula 2; the extraction is performed by extracting the reaction solution with ethyl acetate and a saturated sodium chloride aqueous solution;

[0022] The column chromatography adopts thin layer chromatography column chromatography; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:0.05-0.25.

[0023] Beneficial effects:

[0024] (1) The present invention provides a novel method for synthesizing 2,5-disubstituted furan compounds, which has the advantages of low cost, green and efficient, safe and non-toxic, and mild reaction conditions. Furthermore, the present invention eliminates the need for the addition of additional catalysts and oxidants, overcomes the harsh reaction conditions in traditional systems, and achieves product synthesis with high atomic and step efficiency, thus having broad application prospects in the synthesis of pharmaceutical products.

[0025] (2) In contrast, the electro-excited free radical tandem cyclization strategy of the present invention omits the pre-functionalization step of the starting materials, effectively simplifies the raw materials and shortens the reaction route, effectively avoiding the use of oxidizing or reducing reagents. Under exogenous oxidation and transition metal-free, mild and practical conditions, a method for the direct electrosynthesis of 2,5-disubstituted furans was developed through the oxidative cyclization between two enaminone molecules.

[0026] (3) Compared with the existing technology, the present invention is efficient and economical, with no metal catalyst and exogenous oxidant residue in the product, short reaction time and route, simple and easy-to-obtain raw materials, no need for pre-functionalization, and high yield; its application in the field of biomedical materials is more competitive. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0028] Figure 1 is the reaction equation in Example 1.

[0029] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the product 2a in Example 1.

[0030] Figure 3 This is the carbon NMR spectrum of product 2a in Example 1.

[0031] Figure 4 is the reaction equation in Example 2.

[0032] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of product 2b in Example 2.

[0033] Figure 6 This is the carbon NMR spectrum of product 2b in Example 2.

[0034] Figure 7 is the reaction equation in Example 3.

[0035] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of product 2c in Example 3.

[0036] Figure 9 This is the carbon NMR spectrum of product 2c in Example 3.

[0037] Figure 10 is the reaction equation in Example 4.

[0038] Figure 11 This is the hydrogen nuclear magnetic resonance spectrum of product 2d in Example 4.

[0039] Figure 12 This is the carbon NMR spectrum of product 2d in Example 4.

[0040] Figure 13 is the reaction equation in Example 5.

[0041] Figure 14 This is the hydrogen nuclear magnetic resonance spectrum of the product 2e in Example 5.

[0042] Figure 15This is the carbon NMR spectrum of product 2e in Example 5.

[0043] Figure 16 This is the NMR fluorine spectrum of product 2e in Example 5.

[0044] Figure 17 is the reaction equation in Example 6.

[0045] Figure 18 This is the hydrogen nuclear magnetic resonance spectrum of the product 2f in Example 6.

[0046] Figure 19 This is the carbon NMR spectrum of product 2f in Example 6.

[0047] Figure 20 is the reaction equation in Example 7.

[0048] Figure 21 This is the hydrogen nuclear magnetic resonance spectrum of product 2g in Example 7.

[0049] Figure 22 This is the carbon NMR spectrum of product 2g in Example 7.

[0050] Figure 23 is the reaction equation in Example 8.

[0051] Figure 24 This is the hydrogen nuclear magnetic resonance spectrum of the product 2h in Example 8.

[0052] Figure 25 This is the carbon NMR spectrum of the product 2h in Example 8.

[0053] Figure 26 is the reaction equation in Example 9.

[0054] Figure 27 This is the hydrogen nuclear magnetic resonance spectrum of the product 2i in Example 9.

[0055] Figure 28 This is the carbon NMR spectrum of product 2i in Example 9.

[0056] Figure 29 This is the NMR fluorine spectrum of product 2i in Example 9.

[0057] Figure 30 is the reaction equation in Example 10.

[0058] Figure 31 This is the hydrogen nuclear magnetic resonance spectrum of the product 2j in Example 10.

[0059] Figure 32 This is the carbon NMR spectrum of product 2j in Example 10.

[0060] Figure 33 This is the NMR fluorine spectrum of product 2j in Example 10.

[0061] Figure 34 is the reaction equation in Example 11.

[0062] Figure 35 This is the hydrogen nuclear magnetic resonance spectrum of the product 2k in Example 11.

[0063] Figure 36 This is the carbon NMR spectrum of product 2k in Example 11.

[0064] Figure 37 is the reaction equation in Example 12.

[0065] Figure 38 This is the hydrogen nuclear magnetic resonance spectrum of the product 2m in Example 12.

[0066] Figure 39 This is the carbon NMR spectrum of product 2m in Example 12.

[0067] Figure 40 This is the NMR fluorine spectrum of product 2m in Example 12. DETAILED DESCRIPTION

[0068] The present invention can be better understood with reference to the following examples.

[0069] The present invention provides a catalyst-free and oxidant-free method for the electrosynthesis of 2,5-disubstituted furans via C-C double bond cleavage free radicals. Enaminone 1, an organic electrolyte, and an acidic additive are dissolved in a solvent to obtain a homogeneous solution. This homogeneous solution is then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum (10 mm x 10 mm x 0.1 mm) cathode. The current is controlled at 10 mA to obtain the 2,5-disubstituted furan compound 2. The reaction equation is as follows:

[0070] .

[0071] Example 1

[0072] The reaction equation of this embodiment 1 is as follows Figure 1 shown.

[0073] At 25°C, 3-(Dimethylamino)-1-phenylprop-2-en-1-one (52.5 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum sheet (10 mm × 10 mm × 0.1 mm) cathode. The reaction was controlled at 10 mA and the reaction time was 90 min. After completion, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford the compound of formula 2a with a conversion of 81%.

[0074] The hydrogen nuclear magnetic resonance spectrum of the product 2a in Example 1 is as follows Figure 2 The carbon NMR spectrum of the product 2a in Example 1 is shown in FIG. Figure 3 shown.

[0075] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 30.1 mg,81%; 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 7.2 Hz, 2H), 7.83 (d, J =7.3 Hz, 2H), 7.62 - 7.59 (m, 1H), 7.54 - 7.50 (m, 2H), 7.47 - 7.43 (m, 2H),7.40 - 7.36 (m, 1H), 7.32 (d, J = 3.7 Hz, 1H), 6.84 (d, J = 3.7 Hz, 1H); 13 CNMR (101 MHz, CDCl3) δ 182.22, 158.47, 151.50, 137.64, 132.44, 129.36,129.31, 128.97, 128.46, 125.17, 122.93, 107.50; HRMS (ESI-TOF) Calcd forC 17 H 13 O2 [M+H] + : 249.0910; found: 249.0872.

[0076] Example 2

[0077] The reaction equation of this embodiment 2 is as follows Figure 4 shown.

[0078] At 25°C, 3-(dimethylamino)-1-(p-tolyl)prop-2-en-1-one (56.7 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum sheet (10 mm × 10 mm × 0.1 mm) cathode. The reaction was controlled at 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford product 2b with an 80% conversion.

[0079] The hydrogen nuclear magnetic resonance spectrum of the product 2b in Example 2 is as follows: Figure 5 The carbon NMR spectrum of product 2b in Example 2 is shown in FIG. Figure 6 shown.

[0080] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 33.1 mg,80%; 1 H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 8.1 Hz, 2H), 7.71 (d, J =8.2 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.25 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 3.7Hz, 1H), 2.45 (s, 3H), 2.39 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 181.84,158.55, 151.43, 143.09, 139.46, 135.04, 129.64, 129.48, 129.12, 126.78,125.10, 122.63, 106.79, 21.66, 21.45; HRMS (ESI-TOF) Calcd for C 19 H17 O2 [M+H] + :277.1223; found: 277.1186.

[0081] Example 3

[0082] The reaction equation of this embodiment 3 is as follows Figure 7 shown.

[0083] At 25°C, 1-(4-(ethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one (60.9 mg, 0.3 mmol, 1 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm x 10 mm x 0.1 mm) cathode. The reaction was controlled at 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford product 2c with a conversion of 83%.

[0084] The hydrogen nuclear magnetic resonance spectrum of the product 2c in Example 3 is as follows Figure 8 The carbon NMR spectrum of the product 2c in Example 3 is shown as follows: Figure 9 shown.

[0085] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 37.8 mg,83%; 1 H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 8.3 Hz, 2H), 7.75 (d, J =8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 3.7 Hz, 1H), 7.28 (d, J =8.3 Hz, 2H), 6.79 (d, J = 3.7 Hz, 1H), 2.78 - 2.67 (m, 4H), 1.28 (dt, J =12.7, 7.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 181.86, 158.58, 151.48, 149.29,145.79, 135.25, 129.58, 128.46, 127.95, 127.00, 125.21, 122.67, 107.31,28.99, 28.80, 15.38, 15.26; HRMS (ESI-TOF) Calcd for C 21 H 21 O2 [M+H] + : 305.1536;found: 305.1515

[0086] Example 4

[0087] The reaction equation of this embodiment 4 is as follows Figure 10 shown.

[0088] At 25°C, 1-(4-(tert-butyl)phenyl)-3-(dimethylamino)prop-2-en-1-one (69.3 mg, 0.3 mmol, 1 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum sheet (10 mm × 10 mm × 0.1 mm) cathode. The reaction was controlled at 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford product 2d with a conversion of 81%.

[0089] The H NMR spectrum of product 2d in Example 4 is shown in Figure 11 The carbon NMR spectrum of product 2d in Example 4 is shown in Figure 12 .

[0090] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 43.2 mg,81%; 1H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 8.5 Hz, 2H), 7.77 (d, J =8.5 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.33 (d, J =3.7 Hz, 1H), 6.79 (d, J = 3.7 Hz, 1H), 1.38 (s, 9H), 1.35 (s, 9H); 13 C NMR(101 MHz, CDCl3) δ 181.77, 158.49, 156.08, 152.64, 151.61, 134.94, 129.34,126.77, 125.89, 125.39, 124.97, 122.63, 106.91, 35.12, 34.86, 31.21, 31.17;HRMS (ESI-TOF) Calcd for C 25 H 29 O2 [M+H] + : 361.2162; found: 361.2101.

[0091] Example 5

[0092] The reaction equation of this embodiment 5 is as follows Figure 13 shown.

[0093] At 25°C, 3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (57.9 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum sheet (10 mm x 10 mm x 0.1 mm) cathode. The reaction was carried out at a controlled current of 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford product 2e with a conversion of 76%.

[0094] The H NMR spectrum of the product 2e in Example 5 is shown in Figure 14 The carbon NMR spectrum of the product 2e in Example 5 is shown in Figure 15 The NMR fluorine spectrum of the product 2e in Example 5 is shown in Figure 16 .

[0095] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 32.4 mg,76%; 1 H NMR (400 MHz, Chloroform-d) δ 8.09 - 8.03 (m, 2H), 7.86 - 7.75 (m,2H), 7.32 (d, J = 3.7 Hz, 1H), 7.24 - 7.11 (m, 4H), 6.79 (d, J = 3.7 Hz, 1H); 13 C NMR (101 MHz, Chloroform-d) δ 180.56, 166.73, 164.68, 157.58, 151.37,133.77 (d, J = 4.2 Hz), 131.85 (d, J = 8.8 Hz), 127.11 (d, J = 8.1 Hz),125.68 (d, J = 2.9 Hz), 116.21 (d, J = 22.4 Hz), 115.66 (d, J = 21.8 Hz),107.24; 19 F NMR (376 MHz, CDCl3) δ -105.86, -110.69; HRMS (ESI-TOF) Calcd forC 17 H 11 F2O2 [M+H] + : 285.0722; found: 285.0718.

[0096] Example 6

[0097] The reaction equation of Example 6 is as follows Figure 17 shown.

[0098] At 25°C, 3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (62.7 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm × 10 mm × 0.1 mm) cathode. The reaction was controlled at 10 mA for 90 min. After completion, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford product 2f with a conversion of 78%.

[0099] The H NMR spectrum of the product 2f in Example 6 is shown in Figure 18 The carbon NMR spectrum of the product 2f in Example 6 is shown in Figure 19 .

[0100] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 37.0 mg,78%; 1 H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.86 (m, 2H), 7.78 - 7.64 (m,2H), 7.55 - 7.46 (m, 2H), 7.45 - 7.37 (m, 2H), 7.33 (d, J = 3.7 Hz, 1H), 6.84(d, J = 3.7 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 180.76, 157.43, 151.43,139.01, 135.73, 135.41, 130.71, 129.32, 128.85, 127.74, 126.36, 122.81,107.92; HRMS (ESI-TOF) Calcd for C 17 H 11 Cl2O2 [M+H] + : 317.0131; found: 317.0080.

[0101] Example 7

[0102] The reaction equation of this embodiment 7 is as follows Figure 20 shown.

[0103] At 25°C, 3-(dimethylamino)-1-(4-bromophenyl)prop-2-en-1-one (75.9 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm x 10 mm x 0.1 mm) cathode. The reaction was controlled at 10 mA for 90 min. After completion, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to yield 2 g of the product with an 80% conversion.

[0104] The H NMR spectrum of product 2g in Example 7 is shown in Figure 21 .

[0105] The carbon NMR spectrum of product 2g in Example 7 is shown in Figure 22 .

[0106] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 48.4 mg,80%; 1 H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.83 (m, 2H), 7.70 - 7.64 (m,4H), 7.62 - 7.55 (m, 2H), 7.32 (d, J = 3.7 Hz, 1H), 6.85 (d, J = 3.7 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 180.92, 157.49, 151.41, 136.15, 132.26, 131.83,130.82, 128.14, 127.63, 125.90, 123.68, 122.86, 108.02; HRMS (ESI-TOF) Calcdfor C 17 H 11 Br2O2 [M+H] + : 404.9120; found: 404.9094.

[0107] Example 8

[0108] The reaction equation of Example 8 is as follows Figure 23 shown.

[0109] At 25°C, 3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one (61.5 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm x 10 mm x 0.1 mm) cathode. The reaction was carried out at a controlled current of 10 mA for 90 min. After completion, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to obtain product 2h with a conversion of 82%.

[0110] Figure 24 This is the hydrogen nuclear magnetic resonance spectrum of the product 2h in Example 8.

[0111] Figure 25 This is the carbon NMR spectrum of the product 2h in Example 8.

[0112] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 37.9 mg,82%; 1 H NMR (400 MHz, Chloroform-d) δ 8.11 - 7.98 (m, 2H), 7.78 - 7.71 (m,2H), 7.30 (d, J = 3.7 Hz, 1H), 7.06 - 6.89 (m, 4H), 6.70 (d, J = 3.7 Hz, 1H),3.90 (s, 3H), 3.86 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 180.68, 163.10, 160.49,158.23, 151.40, 131.63, 130.38, 126.66, 122.44, 122.38, 114.41, 113.71,105.98, 55.49, 55.41; HRMS (ESI-TOF) Calcd for C 19 H 17 O4 [M+H] + : 309.1121;found: 309.1081.

[0113] Example 9

[0114] The reaction equation of this embodiment 9 is as follows Figure 26 shown.

[0115] 3-(Dimethylamino)-1-(4-oxytrifluoromethylphenyl)prop-2-en-1-one (77.7 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) at 25°C to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm × 10 mm × 0.1 mm) cathode. The reaction was carried out at a controlled current of 10 mA for 90 min. After completion, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate as eluent and dried under vacuum for 4 h to afford product 2i with a conversion of 77%.

[0116] Figure 27 This is the hydrogen nuclear magnetic resonance spectrum of the product 2i in Example 9.

[0117] Figure 28 This is the carbon NMR spectrum of product 2i in Example 9.

[0118] Figure 29 This is the NMR fluorine spectrum of product 2i in Example 9.

[0119] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 48.0 mg,77%; 1H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.7 Hz, 2H), 7.84 (d, J =8.8 Hz, 2H), 7.39 - 7.34 (m, 3H), 7.31 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 3.7Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 180.40, 157.19, 152.30, 152.29, 151.55,149.85, 149.84, 135.62, 131.25, 127.89, 126.68, 122.87, 121.45, 120.42,108.07; 19 F NMR (376 MHz, CDCl3) δ -57.57, -57.77; HRMS (ESI-TOF) Calcd forC 19 H 11 F6O4 [M+H] + : 417.0556; found: 417.0474.

[0120] Example 10

[0121] The reaction equation of this embodiment 10 is as follows Figure 30 shown.

[0122] At 25°C, 3-(dimethylamino)-1-(4-trifluoromethylphenyl)prop-2-en-1-one (72.9 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum sheet (10 mm x 10 mm x 0.1 mm) cathode. The reaction was controlled at 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to afford product 2j with a conversion of 75%.

[0123] Figure 31 This is the hydrogen nuclear magnetic resonance spectrum of the product 2j in Example 10.

[0124] Figure 32 This is the carbon NMR spectrum of product 2j in Example 10.

[0125] Figure 33 This is the NMR fluorine spectrum of product 2j in Example 10.

[0126] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 43.2 mg,75%; 1 H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.3 Hz, 2H), 7.92 (d, J =8.2 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.37 (d, J =3.8 Hz, 1H), 6.98 (d, J = 3.7 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 180.95,157.10, 151.68, 140.27, 134.22, 133.89, 132.25, 131.32, 131.00, 129.56,126.09 (q, J = 3.9 Hz), 125.64, 125.59 (q, J = 3.7 Hz), 123.11, 109.29; 19 FNMR (376 MHz, CDCl3) δ -62.82, -63.03; HRMS (ESI-TOF) Calcd for C 19 H 11 F6O2 [M+H] + : 385.0658; found: 385.0563.

[0127] Example 11

[0128] The reaction equation of this embodiment 11 is as follows Figure 34 shown.

[0129] At 25°C, 3-(dimethylamino)-1-(2-methylphenyl)prop-2-en-1-one (56.7 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm × 10 mm × 0.1 mm) cathode. The reaction was carried out at a controlled current of 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to obtain product 2k with a conversion of 78%.

[0130] Figure 35 This is the hydrogen nuclear magnetic resonance spectrum of the product 2k in Example 11.

[0131] Figure 36 This is the carbon NMR spectrum of product 2k in Example 11.

[0132] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 32.3 mg,78%; 1 H NMR (400 MHz, Chloroform-d) δ 7.80 - 7.78 (m, 2H), 7.70 - 7.58 (m,2H), 7.42 - 7.39 (m, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 3.7 Hz, 1H),7.20 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 3.7 Hz, 1H), 2.45 (s, 3H), 2.42 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 182.47, 158.69, 151.39, 138.70, 138.32,137.74, 133.17, 130.18, 129.79, 129.30, 128.84, 128.26, 126.48, 125.76,123.03, 122.38, 107.33, 21.44; HRMS (ESI-TOF) Calcd for C 19 H17 O2 [M+H] + :277.1223; found: 277.1181.

[0133] Example 12

[0134] The reaction equation of this embodiment 12 is as follows Figure 37 shown.

[0135] At 25°C, 3-(dimethylamino)-1-(2-fluorophenyl)prop-2-en-1-one (57.9 mg, 0.3 mmol, 1.0 equiv), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equiv), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equiv) were dissolved in ACN / H₂O (7 / 1, 8 mL) to obtain a homogeneous solution. This solution was then added to a 10 mL three-necked round-bottom flask equipped with an RVC (10 mm x 10 mm x 12 mm) anode and a platinum foil (10 mm x 10 mm x 0.1 mm) cathode. The reaction was carried out at a controlled current of 10 mA for 90 min. After completion of the reaction, the product was identified by TLC. The solvent was removed in vacuo. The product was separated using a 10:1 ratio of petroleum ether to ethyl acetate, and dried under vacuum for 4 h to obtain product 2m with a conversion of 78%.

[0136] Figure 38 This is the hydrogen nuclear magnetic resonance spectrum of the product 2m in Example 12.

[0137] Figure 39 This is the carbon NMR spectrum of product 2m in Example 12.

[0138] Figure 40 This is the NMR fluorine spectrum of product 2m in Example 12.

[0139] Yellow solid; Eluent: petroleum ether / ethyl acetate 10:1; 32.4 mg,76%; 1H NMR (400 MHz, Chloroform-d) δ 7.82 (dt, J = 7.8, 1.3 Hz, 1H), 7.71 (ddd, J = 9.3, 2.6, 1.5 Hz, 1H), 7.60 (dt, J = 7.8, 1.3 Hz, 1H), 7.54 - 7.48(m, 2H), 7.45 - 7.40 (m, 1H), 7.36 - 7.29 (m, 2H), 7.09 (tdd, J = 8.4, 2.6,1.0 Hz, 1H), 6.89 - 6.87 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 180.59, 164.11(d, J = 52.3 Hz), 161.65 (d, J = 53.3 Hz), 157.29 (d, J = 3.5 Hz), 151.40,139.31 (d, J = 6.6 Hz), 131.21 (d, J = 8.6 Hz), 130.73 (d, J = 8.6 Hz), 130.22 (d, J = 7.9 Hz), 125.04 (d, J = 3.5 Hz), 122.95, 120.88 (d, J = 3.4Hz), 119.61 (d, J = 21.5 Hz), δ 116.41 (d, J = 15.9 Hz), 116.19 (d, J = 17.4Hz), 112.08 (d, J = 23.4 Hz), 108.45; 19 F NMR (376 MHz, CDCl3) δ -111.78, -111.88; HRMS (ESI-TOF) Calcd for C 17 H 11 F2O2 [M+H] + : 285.0722; found: 285.0724.

[0140] Comparative Example 1

[0141] (Z)-enynol reacts with IBX in DMSO at 90°C for 4.5 hours to produce 2-benzoyl-5-phenylfuran in a 79% yield. After the reaction, the crude product is evaporated. The residue is directly distilled in vacuo and chromatographed on a silica gel column using increasingly polar petroleum ether-ethyl acetate mixtures. However, the high reaction temperature makes this method highly hazardous.

[0142] Comparative Example 2

[0143] (Z)-1,5-Diphenylpent-2-en-4-yn-1-ol, PIFA, I₂, and NaHCO₃ were mixed in THF and stirred at room temperature for 2 hours. After the reaction, the crude product was evaporated. The residue was directly distilled in vacuo and chromatographed on a silica gel column using increasingly polar petroleum ether-ethyl acetate mixtures. However, the use of a strong oxidant limited the environmental and economic practicality of this method.

[0144] Table 1 shows the 2,5-disubstituted furan compounds prepared in various embodiments of the present invention.

[0145] Table 1

[0146]

[0147] The present invention provides a method and concept for the tandem electrosynthesis of 2,5-disubstituted furans via C-C double bond cleavage free radicals. Numerous methods and approaches exist for implementing this technical solution. The foregoing description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. A method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals, characterized in that: The steps include: (1) dissolving the enaminone represented by formula 1, an organic electrolyte, and an acidic additive in a solvent to obtain a homogeneous solution; (2) adding the homogeneous solution in step (1) into an electrochemical reaction device, reacting sufficiently, and collecting the product shown in formula 2 to obtain; The above reaction equation is: ； Among them, R 1 is an electron-donating group or an electron-withdrawing group; the electron-donating group is selected from any one of hydrogen, 1-4 C alkyl, methoxy or trifluoromethoxy; the electron-withdrawing group is selected from any one of halogen and trifluoromethyl; In step (2), the current intensity of the electrochemical reaction device is 8-20 mA, the reaction temperature is 20-80°C, and the reaction time is 90-150 min.

2. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the acidic additive is selected from one or a mixture of two or more of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, lithium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and nickel trifluoromethanesulfonate.

3. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the organic electrolyte is selected from one or a mixture of two or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroacetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroiodide, and tetrabutylammonium tetrafluoroperchlorate.

4. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the solvent is selected from one or a mixture of two or more of dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, N,N-dimethylaniline, tetrahydrofuran, water, methanol, and ethanol.

5. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the molar ratio of the enaminone, the acidic additive, and the organic electrolyte is (1-2): 2:

2.

6. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the concentration of enaminone in the obtained homogeneous solution is 0.03 - 0.12 mmol / mL.

7. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the concentration of the acidic additive in the obtained homogeneous solution is 0.03-0.12 mmol / mL.

8. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (1), the concentration of the organic electrolyte in the obtained homogeneous solution is 0.06-0.12 mmol / mL.

9. The method for synthesizing 2,5-disubstituted furans by tandem electrolysis of C-C double bond cleavage free radicals according to claim 1, characterized in that: In step (2), the reaction solution obtained after the reaction is completed is extracted to obtain an organic phase, which is concentrated and subjected to column chromatography to obtain the product shown in Formula 2; the extraction is performed by extracting the reaction solution with ethyl acetate and a saturated sodium chloride aqueous solution; The column chromatography adopts thin layer chromatography column chromatography; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1:0.05-0.25.

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