Method for synthesizing furan derivative under catalysis of copper

Abstract

The invention discloses a method for synthesizing furan derivatives under the catalysis of copper, which comprises the following steps: in an organic solvent system, by taking silyl enol ether compounds as shown in a formula (1) as raw materials, metal copper salt as a catalyst, metal silver salt as a cocatalyst, metal potassium salt as alkali and tert-butyl peroxide as a free radical initiator, stirring and reacting at 120 DEG C, and tracking and detecting through TLC (Thin Layer Chromatography) until the reaction is complete, thereby obtaining the furan derivatives. And performing post-treatment on the reaction liquid to obtain the furan derivative as shown in the formula (2). The method is simple to operate, reagents are easy to obtain, reaction conditions are mild, a reaction system is green and environment-friendly, products are easy to separate and purify, the method is suitable for synthesizing various highly-functionalized furan derivatives, and the high-purity furan derivatives can be efficiently prepared.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical organic synthesis technology, specifically relating to a method for copper-catalyzed synthesis of furan derivatives. Background Technology

[0002] Furan skeletons are ubiquitous in natural products and functional material molecules, and are widely used in agricultural chemistry and medicinal chemistry. For example, nitrofurazone is an organic compound used as a disinfectant and antiseptic, clinically for treating wounds, burns, purulent dermatitis, otitis media, and dacryocystitis; furazolidone is a nitrofuran antibiotic used to treat gastrointestinal diseases such as dysentery, enteritis, and gastric ulcers caused by bacteria and protozoa; furadantin is an excellent antibacterial drug with a broad antibacterial spectrum, rapid and complete absorption after oral administration, and is often used to treat urinary tract infections caused by various susceptible bacteria. Therefore, exploring different methods to synthesize diverse furan compounds is a hot topic in organic synthesis research, with broad prospects and significant importance.

[0003] Current methods for synthesizing furans have some drawbacks, such as a narrow substrate range and demanding reaction conditions. Therefore, developing a novel and practical method for synthesizing furan compounds is of great significance. Summary of the Invention

[0004] The purpose of this invention is to provide a copper-catalyzed method for synthesizing furan derivatives. This method is simple to operate, uses readily available reagents, has mild reaction conditions, and yields high product yields.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for copper-catalyzed synthesis of furan derivatives, wherein in an organic solvent system, an enol silyl ether compound of formula (1) is used as the raw material, with copper salt as the catalyst, silver salt as the co-catalyst, potassium salt as the base, and tert-butyl peroxide as the free radical initiator, and the reaction is stirred at 120°C. The reaction is monitored by TLC until the reaction is complete, and the furan derivative of formula (2) is obtained after post-treatment of the reaction solution. The organic solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The copper salt is one of cuprous iodide, cuprous bromide, cuprous oxide, and copper oxide; The silver salt is one of silver carbonate, silver bromide, and silver oxide; The potassium salt is one of potassium iodide, potassium bromide, and potassium carbonate. The tert-butyl peroxide is one of DTBP, TBHP, and TBPB; Among them, R 1 It is one of -Cl, -Br, -Me, and -H; R 2 It can be either -H or -Me.

[0006] Preferably, the copper salt is cuprous iodide, the silver salt is silver carbonate, the potassium salt is potassium iodide, and the tert-butyl peroxide is DTBP.

[0007] Preferably, the amount of copper salt and silver salt is 20 mol of the amount of enol silyl ether compound shown in formula (1), the amount of potassium salt is 50 mol of the amount of enol silyl ether compound shown in formula (1), and the amount of tert-butyl peroxide is 200 mol of the amount of enol silyl ether compound shown in formula (1).

[0008] Preferably, the organic solvent is N,N-dimethylformamide.

[0009] Preferably, the amount of the organic solvent used is 5 mL / mmol of the amount of the enol silyl ether compound represented by formula (1).

[0010] Preferably, the developing solvent used for TLC tracking reaction is petroleum ether: ethyl acetate = 20: 1, V / V.

[0011] Further, the post-treatment method of the reaction solution is as follows: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, then the organic phase is backwashed with water, dried with anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography. The eluent is distilled under reduced pressure and dried to obtain the furan derivative shown in formula (2).

[0012] Preferably, the eluent for the silica gel column chromatography is petroleum ether: ethyl acetate = 20: 1, V / V.

[0013] Compared with the prior art, the present invention has the following beneficial effects: This invention employs an unprecedented copper-catalyzed three-component reaction of enol silyl ether compounds to synthesize furan derivatives, providing a convenient modular method for synthesizing furan derivatives. This invention uses a copper salt as a catalyst, employs a one-pot method, is simple to operate, uses readily available reagents, operates under mild reaction conditions, has a green and environmentally friendly reaction system, and produces easily separated and purified products. It is suitable for synthesizing various highly functionalized furan derivatives, and is particularly suitable for large-scale industrial production, enabling the efficient and high-yield production of high-purity furan derivatives. Attached Figure Description

[0014] Figure 1The furan derivative 2a prepared in Example 1 of this invention 1 H-NMR nuclear magnetic resonance spectrum; Figure 2 The furan derivative 2a prepared in Example 1 of this invention 13 C-NMR nuclear magnetic resonance spectrum; Figure 3 The furan derivative 2b prepared in Example 2 of this invention 1 H-NMR nuclear magnetic resonance spectrum; Figure 4 The furan derivative 2b prepared in Example 2 of this invention 13 C-NMR nuclear magnetic resonance spectrum; Figure 5 The furan derivative 2c prepared in Example 3 of this invention 1 H-NMR nuclear magnetic resonance spectrum; Figure 6 The furan derivative 2c prepared in Example 3 of this invention 13 C-NMR nuclear magnetic resonance spectrum; Figure 7 The furan derivative 2d prepared in Example 4 of this paper 1 H-NMR nuclear magnetic resonance spectrum; Figure 8 The furan derivative 2d prepared in Example 4 of this paper 13 C-NMR nuclear magnetic resonance spectrum; Figure 9 The furan derivative 2e prepared in Example 5 of this invention 1 H-NMR nuclear magnetic resonance spectrum; Figure 10 The furan derivative 2e prepared in Example 5 of this invention 13 C-NMR nuclear magnetic resonance spectrum; Figure 11 The furan derivative 2f prepared in Example 6 of this invention 1 H-NMR nuclear magnetic resonance spectrum; Figure 12 The furan derivative 2f prepared in Example 6 of this invention 13 C-NMR nuclear magnetic resonance spectrum Figure 13 2g of the furan derivative prepared in Example 7 of this study 1 H-NMR nuclear magnetic resonance spectrum; Figure 14 2g of the furan derivative prepared in Example 7 of this study 13 C-NMR nuclear magnetic resonance spectrum Figure 15 The furan derivative prepared in Example 8 of this study was 2h 1H-NMR nuclear magnetic resonance spectrum; Figure 16 The furan derivative prepared in Example 8 of this study was 2h 13 C-NMR nuclear magnetic resonance spectrum. Detailed Implementation

[0015] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0016] Example 1: Preparation of furan derivative 2a Add enol silyl ether compound 1a (67 µL, 0.4 mmol), cuprous iodide (15 mg, 20 mmol%), silver carbonate (22 mg, 20 mmol%), potassium iodide (34 mg, 50 mmol%), DTBP (148 µL, 200 mmol%), and N,N-dimethylformamide (2 mL) to a 10 mL Shrek flask equipped with a magnetic stirrer. After thorough mixing, place the flask in a 120°C oil bath and continue stirring. TLC (developing solvent: V) 石油醚 V 乙酸乙酯 = 20 : 1) The reaction ends when the substrate disappears. Pour the reaction solution into water (30 mL), extract with ethyl acetate (3 × 10 mL), combine the organic phases, then backwash the organic phase with water (3 × 10 mL), and obtain a viscous solid by drying with anhydrous sodium sulfate, filtration, and vacuum distillation. Finally, perform silica gel column chromatography (elution buffer V) 石油醚 V 乙酸乙酯 = 20 : 1) A white solid was obtained, which was confirmed by NMR and MS to be furan derivative 2a, with a yield of 71%.

[0017] Hydrogen and carbon spectra are as follows Figure 1 and Figure 2 As shown, the spectral analysis data is as follows 2a: Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.99-7.97 (m, 2H), 7.86-7.80 (m, 4H), 7.58-7.38 (m, 9H), 7.03 (s, 1H) ( Figure 1 ) 13 C NMR (101 MHz, Chloroform-d): δ C165.3, 157.0, 136.9, 134.6, 133.5, 132.9, 129.7, 129.6, 129.2, 128.7, 128.5, 128.4, 125.1, 108.1 Figure 2 ); HRMS (ESI-TOF, m / z): calcd forC 24 H 16 O3[M + H] + , 353.1172; found, 353.1175. Example 2: Using 1b instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 96%.

[0018] Hydrogen and carbon spectra are as follows Figure 3 and Figure 4 As shown in Figure 2b, the spectral analysis data is as follows: Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.93-7.91 (m, 2H), 7.76 (d,J = 6.8 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.28-7.18 (m, 6H), 6.93 (s, 1H) ,2.41 (s, 6H) , 2.37(s, 3H)( Figure 3 ) 13 C NMR (101 MHz, Chloroform-d): δ C 191.0, 181.1, 156.9, 148.8, 144.4, 143.7, 139.8, 134.6, 134.5, 134.1, 129.8, 129.7, 129.4, 129.2, 129.0, 126.1, 125.0, 107.4, 21.7, 21.6, 21.4 Figure 4 ); HRMS (ESI-TOF, m / z): calcd for C 27 H 23 O3[M + H] + , 395.1642; found, 395.1644. Example 3: Using 1c instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 91%.

[0019] Hydrogen and carbon spectra are as follows Figure 5 and Figure 6 As shown, the spectral analysis data is as follows (2c): Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.95-7.93 (m, 2H), 7.80-7.78 (m, 2H), 7.72-7.71 (m, 2H), 7.47-7.45 (m, 4H), 7.40-7.39 (m, 2H), 7.01(s, 1H) ( Figure 5 ) 13 C NMR (101 MHz, Chloroform-d): δ C 189.6, 180.1, 156.2, 148.8, 140.3, 139.8, 136.0, 135.1, 134.6, 134.5, 130.9, 130.5, 129.5, 129.0, 128.9, 126.9, 126.3, 108.4 Figure 6 ); HRMS (ESI-TOF, m / z): calcd for C 24 H 13 O3Cl3[M + H] + ,455.0003; found, 455.0008. Example 4: Using 1d instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 80%.

[0020] Hydrogen and carbon spectra are as follows Figure 7 and Figure 8 As shown, the spectral analysis data is as follows (2d): Yellow solid; 11 H NMR (400 MHz, Chloroform-d): δ H 7.86-7.77 (m, 4H), 7.71-7.69 (m, 2H), 7.63-7.61 (m, 4H), 7.57-7.51 (m, 2H), 7.02 (s, 1H) ( Figure 7 ) 13 C NMR (101 MHz, Chloroform-d): δ C189.8, 180.3, 156.2, 148.8, 138.4, 137.9, 137.8, 135.6, 135.0, 134.4, 132.4, 131.9, 131.8, 131.0, 130.8, 130.6, 130.4, 129.1, 128.5, 127.3, 126.5, 124.3, 108.5 Figure 8 ); HRMS (ESI-TOF, m / z): calcd forC 24 H 13 O3Br3[M + H] + , 586.8488; found, 586.8492. Example 5: Using 1e instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 86%.

[0021] Hydrogen and carbon spectra are as follows Figure 9 and Figure 10 As shown, the spectral analysis data is as follows (2e): White solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.66-7.63 (m, 1H), 7.63-7.54 (m, 5H), 7.38–7.29 (m, 4H), 7.26-7.22 (m, 2H), 7.00 (s, 1H), 2.42 (s,3H), 2.33(s, 6H) ( Figure 9 ) 13 C NMR (101 MHz, Chloroform-d): δ C 191.4 182.2, 157.1,149.0, 138.8, 138.30, 138.1, 137.2, 137.0, 134.5, 134.1, 133.5, 130.5, 130.0,129.4, 128.9, 128.7, 128.3, 128.2, 126.7, 126.6, 125.7, 122.3, 107.9, 21.4,21.1 Figure 10 ); HRMS (ESI-TOF, m / z): calcd for C 21 H 19 ClNO5[M + H] +, 395.1642;found, 395.1649. Example 6: Using 1f instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 92%.

[0022] Hydrogen and carbon spectra are as follows Figure 11 and Figure 12 As shown, the spectral analysis data is as follows (2f): Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.91 (s, 1H), 7.84–7.83 (m,1H), 7.78–7.76 (m, 2H), 7.69–7.67 (m, 2H), 7.57–7.52 (m, 2H), 7.45–7.33 (m,4H), 7.05 (s, 1H) ( Figure 11 ) 13 C NMR (101 MHz, Chloroform-d) δ C 189.4, 180.1, 155.9, 148.9, 138.3, 137.8, 135.3, 135.0, 134.8, 134.3, 133.6, 133.1, 130.5, 130.0, 129.9, 129.9, 129.8, 129.5, 128.9, 127.5, 127.2, 125.1, 123.2, 108.9 Figure 12 );;HRMS (ESI-TOF, m / z): calcd for C 37 H 30 ClN2O3[M + H] + , 455.0003; found, 455.0007. Example 7: Using 1g instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 95%.

[0023] Hydrogen and carbon spectra are as follows Figure 13 and Figure 14 As shown, the spectral analysis data is as follows (2g): Yellow oily substance; 1 H NMR (400 MHz, Chloroform-d): δ H7.80–7.79 (m, 1H), 7.44–7.72 (m, 1H), 7.38–7.36 (m, 1H), 7.32–7.24 (m, 5H), 7.14–7.10 (m, 3H), 7.06–7.04 (m, 1H), 6.95 (s, 1H) , 2.55 (s, 3H) , 2.40 (s, 3H) , 2.19 (s, 3H) ( Figure 13 ) 13 C NMR (101 MHz, Chloroform-d) δ C 192.5, 184.9, 156.8, 149.1, 139.8, 137.9, 137.3, 137.1, 135.9, 134.7, 132.0, 131.8, 131.6, 131.2, 131.1, 131.0, 129.5, 129.1, 128.0, 128.0, 126.3, 125.3, 125.2, 111.5, 21.9, 21.3, 19.9 Figure 14 ); HRMS (ESI-TOF, m / z): calcd for C 36 H 27 Cl2N2O2[M + H] + , 395.1642; found, 395.1644. Example 8: Using 1h instead of 1a in Example 1, with other conditions the same as in Example 1, the yield was 92%.

[0024] Hydrogen and carbon spectra are as follows Figure 15 and Figure 16 As shown, the spectral analysis data is as follows (2h): Yellow oily substance; 1 H NMR (400 MHz, Chloroform-d): δ H 7.80–7.78 (m, 1H), 7.59–7.58 (m, 2H), 7.48–7.47 (m, 1H), 7.43–7.36 (m, 5H), 7.33–7.28 (m, 5H) ( Figure 15 ) 13 C NMR (101MHz, Chloroform-d) δ C13C NMR (101 MHz, CDCl3) δ 189.2, 182.0,153.3, 148.7, 137.5, 137.0, 133.6, 132.5, 132.4, 132.3, 132.1, 131.7, 131.0,130.9, 130.7, 130.3, 130.2, 130.1, 128.9, 127.2, 127.1, 126.8, 126.7, 114.1 ( Figure 16 ); HRMS (ESI-TOF, m / z): calcd for C 37 H 30 BrN2O2[M + H] + , 455.0003; found, 455.0009. This invention, based on the synthesis of a furan skeleton, incorporates a 1,4-diketone structure, and this highly functionalized 1,4-diketone can serve as a starting material for the synthesis of heterocycles. For example, by reacting with hydrazine hydrate (reaction 1) and hydroxylamine hydrochloride (reaction 2), furan derivative 2b can be converted into functionalized furanopyridazine 3a and 1,4-dioxime 3b in high yield.

[0025] The spectral analysis data for proton and carbon spectra are as follows: 3a: Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 7.81-7.80 (m, 2H), 7.62-7.59 (m, 2H), 7.32-7.28 (m, 2H), 7.25-7.09 (m, 6H), 6.56 (s, 1H), 2.42 (s,6H), 2.35(s, 3H); 13 C NMR (101 MHz, Chloroform-d): δ C 155.7, 153.9, 151.3,147.8, 143.1, 141.7, 140.8, 135.6, 135.5, 135.1, 130.8, 130.5, 130.0., 129.7,129.5, 126.8, 125.5, 110.4, 20.9, 20.8, 20.5; HRMS (ESI-TOF, m / z): calcd forC 27 H 23 O3[M + H] +, 391.1805; found, 391.1817. The spectral analysis data for proton and carbon spectra are shown in 3b below: Yellow solid; 1 H NMR (400 MHz, Chloroform-d): δ H 11.23 (s, 1H), 10.78 (s,1H), 7.92-7.91 (m, 2H), 7.76 (d, J = 6.8 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H),7.39-7.21 (m, 6H), 6.71 (s, 1H) , 2.39 (s, 6H) , 2.34(s, 3H) ; 13 C NMR (101MHz, Chloroform-d): δ C 169.1, 154.2, 152.3, 146.8, 142.1, 140.7, 137.8, 133.6,133.5, 133.1, 129.8, 129.7, 129.4, 129.2, 129.0, 126.1, 125.0, 107.4, 21.4,21.3, 20.8; HRMS (ESI-TOF, m / z): calcd for C 27 H 23 O3[M + H] + , 425.1860; found,425.1688.

Claims

1. A method for copper-catalyzed synthesis of furan derivatives, characterized in that, In an organic solvent system, using the enol silyl ether compound shown in formula (1) as the raw material, with copper salt as the catalyst, silver salt as the co-catalyst, potassium salt as the base, and tert-butyl peroxide as the free radical initiator, the reaction was stirred at 120°C and monitored by TLC until the reaction was complete. After the reaction solution was treated, the furan derivative shown in formula (2) was obtained. The organic solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The copper salt is one of cuprous iodide, cuprous bromide, cuprous oxide, and copper oxide; The silver salt is one of silver carbonate, silver bromide, and silver oxide; The potassium salt is one of potassium iodide, potassium bromide, and potassium carbonate. The tert-butyl peroxide is one of DTBP, TBHP, and TBPB; Among them, R 1 It is one of -Cl, -Br, -Me, and -H; R 2 It can be either -H or -Me.

2. The method for copper-catalyzed synthesis of furan derivatives according to claim 1, characterized in that, The copper salt is cuprous iodide, the silver salt is silver carbonate, the potassium salt is potassium iodide, and the tert-butyl peroxide is DTBP.

3. The method for copper-catalyzed synthesis of furan derivatives according to claim 1, characterized in that, The amount of copper salt and silver salt used is 20 mol of the amount of enol silyl ether compound shown in formula (1), the amount of potassium salt used is 50 mol of the amount of enol silyl ether compound shown in formula (1), and the amount of tert-butyl peroxide used is 200 mol of the amount of enol silyl ether compound shown in formula (1).

4. The method for copper-catalyzed synthesis of furan derivatives according to claim 1, characterized in that, The organic solvent is N,N-dimethylformamide.

5. The method for copper-catalyzed synthesis of furan derivatives according to claim 1, characterized in that, The amount of the organic solvent used is 5 mL / mmol of the amount of the enol silyl ether compound shown in formula (1).

6. The method for copper-catalyzed synthesis of furan derivatives according to claim 1, characterized in that, The developing solvent used for TLC tracking of the reaction was petroleum ether: ethyl acetate = 20: 1, V / V.

7. The method for copper-catalyzed synthesis of furan derivatives according to claim 1, characterized in that, The post-treatment method of the reaction solution is as follows: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried with anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography. The eluent is distilled under reduced pressure and dried to obtain the furan derivative shown in formula (2).

8. The method for copper-catalyzed synthesis of furan derivatives according to claim 7, characterized in that, The eluent for the silica gel column chromatography was petroleum ether: ethyl acetate = 20: 1, V / V.

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