Method for series electrosynthesis of 2, 5-disubstituted furan by cracking free radicals through C-C double bonds

Abstract

The invention discloses a method for series electrosynthesis of 2, 5-disubstituted furan by cracking free radicals through C-C double bonds, which comprises the following steps: dissolving enaminone, an organic electrolyte and an acidic additive in a solvent to obtain a homogeneous solution; and adding the homogeneous solution into an electrochemical reaction device, fully reacting, and collecting to obtain a product. Compared with the prior art, the synthesis process has the advantages of low operation cost, greenness, high efficiency, safety, no toxicity, mild reaction conditions and the like. Meanwhile, other catalysts and oxidants do not need to be additionally added, the problems that in a traditional system, reaction conditions are harsh and the like are solved, product synthesis is achieved in a high-atom and stepwise mode, and the method has wide application prospects in the aspect of medicine product synthesis.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and fine chemical synthesis, and specifically relates to a method for tandem electrosynthesis of 2,5-disubstituted furans through CC 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 flavor and fragrance industries. 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 some 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 multi-step pre-functionalization. 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 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 provide a method for tandem electrosynthesis of 2,5-disubstituted furans by CC double bond cleavage free radicals in view of the deficiencies in the prior art, so as to solve the problems of low yield and selectivity, use of stoichiometric oxidants and multi-step pre-functionalization in the prior art.

[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 electrosynthesis of CC 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, it is any one or a combination of tetrabutylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroacetate, tetrabutylammonium hexafluorophosphate, and tetrabutylammonium tetrafluoroiodide; more preferably, it is tetrabutylammonium hexafluorophosphate and tetrabutylammonium tetrafluoroborate; and more preferably, it is 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, it is any one or a combination of dimethyl sulfoxide, trifluoroethanol, acetonitrile, hexafluoroisopropanol, N,N-dimethylaniline, and water; more preferably, it is trifluoroethanol, acetonitrile, hexafluoroisopropanol, and water; and more preferably, it is 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; 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), 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 a 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, mild reaction conditions, etc. At the same time, the present invention does not need to add other catalysts and oxidants, overcomes the problems of harsh reaction conditions in traditional systems, and achieves product synthesis with high atomic and step efficiency, which has 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 avoids the use of oxidizing or reducing agents, and develops a method for the direct electrosynthesis of 2,5-disubstituted furans through oxidative cyclization between two enaminone molecules under exogenous oxidation and transition metal-free, mild and practical conditions.

[0026] (3) Compared with the prior art, 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 in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[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 It 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 It is the reaction equation in Example 3.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0067] Fig.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 method for synthesizing 2,5-disubstituted furan by tandem electrocatalysis of CC double bond cleavage free radicals under catalyst-free and oxidant-free conditions. Enaminoketone 1, an organic electrolyte, and an acidic additive are dissolved in a solvent to obtain a homogeneous solution; the homogeneous solution is 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, and the current is controlled to be 10 mA, thereby obtaining a 2,5-disubstituted furan compound 2, and 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 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to be 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of 10:1 petroleum ether and ethyl acetate, and the obtained product was dried in vacuo for 4 h to obtain the compound shown in formula 2a with a conversion rate 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 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 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain product 2b with a conversion rate of 80%.

[0079] The hydrogen nuclear magnetic resonance spectrum of product 2b in Example 2 is as follows Figure 5 The carbon NMR spectrum of product 2b in Example 2 is shown in 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 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain product 2c with a conversion rate of 83%.

[0084] The hydrogen NMR spectrum of product 2c in Example 3 is as follows Figure 8 The carbon NMR spectrum of the product 2c in Example 3 is shown in Fig. 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 Fig.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 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain product 2d with a conversion rate of 81%.

[0089] The hydrogen NMR spectrum of product 2d in Example 4 is shown in Fig.11 The carbon NMR spectrum of product 2d in Example 4 is shown in Fig.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 Fig.13 shown.

[0093] At 25 °C, 3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (57.9 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain the product 2e with a conversion rate of 76%.

[0094] The hydrogen NMR spectrum of the product 2e in Example 5 is shown in Fig.14 The carbon NMR spectrum of the product 2e in Example 5 is shown in Fig.15 The NMR fluorine spectrum of the product 2e in Example 5 is shown in Fig.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 this embodiment 6 is as follows Fig.17 shown.

[0098] At 25 °C, 3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (62.7 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1 and dried in vacuo for 4 h to obtain product 2f with a conversion rate of 78%.

[0099] The hydrogen NMR spectrum of the product 2f in Example 6 is shown in Fig.18 The carbon NMR spectrum of the product 2f in Example 6 is shown in Fig.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 Fig. 20 shown.

[0103] At 25 °C, 3-(dimethylamino)-1-(4-bromophenyl)prop-2-en-1-one (75.9 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain 2 g of the product with a conversion rate of 80%.

[0104] The hydrogen nuclear magnetic resonance spectrum of the product 2g in Example 7 is shown in Fig.21 .

[0105] The carbon NMR spectrum of product 2g in Example 7 is shown in Fig. 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 this embodiment 8 is as follows Fig.23 shown.

[0109] At 25 °C, 3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one (61.5 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain product 2h with a conversion rate of 82%.

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

[0111] Fig.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 Fig.26 shown.

[0115] At 25 °C, 3-(dimethylamino)-1-(4-oxytrifluoromethylphenyl)prop-2-en-1-one (77.7 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution, which was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated by using an eluent of petroleum ether and ethyl acetate in a ratio of 10:1 and dried under vacuum for 4 h to obtain product 2i with a conversion rate of 77%.

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

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

[0118] Fig.29 This is the NMR fluorine spectrum of the 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 Fig.30 shown.

[0122] At 25 °C, 3-(dimethylamino)-1-(4-trifluoromethylphenyl)prop-2-en-1-one (72.9 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain product 2j with a conversion rate of 75%.

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

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

[0125] Fig.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] Embodiment 11

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

[0129] At 25 °C, 3-(dimethylamino)-1-(2-methylphenyl)prop-2-en-1-one (56.7 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain the product 2k with a conversion rate of 78%.

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

[0131] Fig.36 This is the carbon NMR spectrum of the 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 Fig.37 shown.

[0135] At 25 °C, 3-(dimethylamino)-1-(2-fluorophenyl)prop-2-en-1-one (57.9 mg, 0.3 mmol, 1.0 equivalent), p-toluenesulfonic acid (51.7 mg, 0.3 mmol, 1.0 equivalent), and tetrabutylammonium hexafluorophosphate (232.4 mg, 0.6 mmol, 2.0 equivalent) were dissolved in ACN / H2O (7 / 1, 8 mL) to obtain a homogeneous solution. The homogeneous solution was 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 current was controlled to 10 mA and the reaction time was 90 min. After the reaction was completed, the product was identified by TLC. The solvent was removed in vacuo. The product was separated with an eluent of petroleum ether and ethyl acetate in a ratio of 10:1, and the obtained product was dried in vacuo for 4 h to obtain the product 2m with a conversion rate of 78%.

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

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

[0138] Fig.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 h to give 2-benzoyl-5-phenylfuran in 79% yield. After the reaction, the crude product is evaporated. The residue is distilled directly in vacuo and chromatographed on a silica gel column using a petroleum ether-ethyl acetate mixture of increasing polarity. However, the high reaction temperature makes this method more dangerous.

[0142] Comparative Example 2

[0143] (Z)-1,5-diphenylpent-2-ene-4-yn-1-ol, PIFA, I2, and NaHCO3 were mixed in THF and stirred at room temperature for 2 h. After the reaction was completed, the crude product was evaporated. The residue was directly distilled in a vacuum and chromatographed on a silica gel column using a petroleum ether-ethyl acetate mixture with increasing polarity. However, since a strong oxidant was used in the reaction, the green economic practicability of this method was very low.

[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 idea for synthesizing 2,5-disubstituted furan by tandem electrosynthesis of CC double bond cleavage free radicals. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be considered as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for synthesizing 2,5-disubstituted furans by tandem electrosynthesis of CC 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.

2. The method for synthesizing 2,5-disubstituted furans by tandem electrosynthesis of CC 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 electrosynthesis of CC 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 electrosynthesis of CC 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 electrosynthesis of CC 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 tandem electrosynthesis of 2,5-disubstituted furans by CC 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 electrosynthesis of CC 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 tandem electrosynthesis of 2,5-disubstituted furans by CC 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 tandem electrosynthesis of 2,5-disubstituted furans by CC double bond cleavage free radicals according to claim 1, characterized in that: 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.

10. The method for tandem electrosynthesis of 2,5-disubstituted furans by CC 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 a 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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