Method for preparing dihydrofuran-containing compound by using alpha-halogenated ester

Abstract

The invention discloses a method for preparing a dihydrofuran-containing compound by using alpha-halogenated ester, which comprises the following steps of: adding 2-chloro-3-oxo-3-methyl phenylpropionate, 1, 1-disubstituted ethylene, N-methylindole, alkali and lewis acid into an organic solvent, reacting at room temperature under the irradiation of blue light, and then performing chromatography to obtain the dihydrofuran-containing compound. According to the method, methyl 2-chloro-3-oxo-3-phenylpropionate, 1, 1-disubstituted ethylene and N-methylindole are used as reactants, and the dihydrofuran-containing compound is obtained through one-step reaction under room-temperature blue light irradiation. The synthesis method has the advantages of high efficiency, simple conditions, high yield and environmental friendliness, and the target molecule has important application value in the fields of medicines and pesticides.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a method for preparing dihydrofuran compounds using α-haloesters. Background Technology

[0002] Dihydrofuran compounds are widely found in natural products and pharmaceutical active molecules, and are also important organic reactive intermediates. Their outstanding performance in various fields has made the extraction, preparation, and synthesis of dihydrofuran compounds a research hotspot in the food and biological fields. However, existing methods for synthesizing polysubstituted dihydrofuran compounds still have some problems, such as the need for expensive metal catalysts, complex reaction conditions, long reaction times, and limited substrate scope.

[0003] Therefore, it is of great significance to develop efficient, economical, green, and substrate-applicable synthetic methods for dihydrofuran compounds. Summary of the Invention

[0004] Objective of the Invention: To address the technical problems existing in the prior art, this invention provides a method for preparing dihydrofuran-containing compounds using α-haloesters. This invention utilizes EDA complexes to undergo single-electron transfer to form highly reactive radical intermediates. Then, an olefin is used to capture this reactive intermediate in the reaction system, thereby initiating a cyclization reaction to construct important oxygen-containing heterocyclic compounds. This method avoids the need for metal catalysts or photosensitizers in the reaction system, while still allowing the reaction to proceed normally, thus providing a new route for the green synthesis of oxygen-containing heterocyclic compounds.

[0005] Technical Solution: To achieve the above-mentioned objectives, the present invention adopts the following technical solution: A method for preparing dihydrofuran-containing compounds using α-haloesters, wherein, under blue light irradiation catalysis and nitrogen protection, and with the addition of a base, Lewis acid, and solvent, an EDA complex is used as an electron donor to induce a cyclization reaction between the α-haloester and an olefin to prepare dihydrofuran-containing compounds.

[0006] Preferably, the EDA complex is N-methylindole or N-ethylindole.

[0007] Preferably, the α-haloester is methyl 2-chloro-3-oxo-3-phenylpropionate or methyl 2-chloroacetoacetate.

[0008] Preferably, the olefin is 1,1-diphenylethylene.

[0009] Preferably, the alkali is selected from KHCO3, Na2HPO4, and HCOOK; the Lewis acid is selected from Zn(OAc)2 and CuCl; and the solvent is selected from dichloroethane (DCE), acetonitrile (CH3CN), and tetrahydrofuran (THF).

[0010] Preferably, the power of the blue light irradiation is 45-50W, and the wavelength is 460-500nm.

[0011] Preferably, the molar ratio of the reactant α-haloester to olefin is 2.5-3.5:1.

[0012] Preferably, the molar ratio of the amount of the base, Lewis acid and EDA complex added to the olefin is (2.5-3.5):(1.5-2.5):(0.05-0.15):1.

[0013] Preferably, the ratio of the volume of solvent added to the olefin is 1 mL / mmol.

[0014] Preferably, the method for preparing dihydrofuran-containing compounds using α-haloesters includes the following steps: S1, KHCO3 and zinc acetate Zn(OAc)2 are added to the reaction vessel in proportion, and nitrogen is backfilled after vacuuming; S2, add dichloroethane (DCE) solvent in a nitrogen atmosphere, then add methyl 2-chloro-3-oxo-3-phenylpropionate, 1,1-diphenylethylene and N-methylindole in proportion, and mix and stir evenly. S3, place the reaction mixture in a water bath and stir for 12-36 h under 45 W 460 nm blue irradiation catalysis; S4, the reaction mixture was quenched with pure water in the reaction system, then extracted at least once with ethyl acetate (EtOAc), and the crude product was obtained by concentration under reduced pressure; the crude product was then purified by rapid silica gel column chromatography to obtain the purified target product.

[0015] Beneficial Effects: Compared with existing technologies, this invention activates α-haloesters with Zn(OAc)2, thereby achieving the formation of an EDA complex involving Zn(OAc)2, α-haloesters, and N-methylindole. Based on the formation of this EDA complex, we synthesized various dihydrofuran-containing compounds through photocatalytic olefin cyclization reactions involving α-haloesters and N-methylindole. The technical route for preparing dihydrofuran-containing compounds in this invention is simple and efficient. The catalytic system does not require photocatalysts, external oxidants, or reductants, and it directly synthesizes polysubstituted dihydrofuran-containing compounds with high selectivity under redox-neutral conditions, providing a useful method for green organic synthesis. Attached Figure Description

[0017] The accompanying drawings, which form part of this application, are used to provide a further understanding of this application. The illustrative embodiments of this application and their descriptions are used to explain this application and do not constitute an undue limitation of this application.

[0018] Figure 1 This is the reaction equation for preparing dihydrofuran compounds using α-haloesters in this invention.

[0019] Figure 2 This is a reaction mechanism diagram of the present invention for preparing dihydrofuran-containing compounds using α-haloesters. Detailed Implementation

[0021] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. After reading the present invention, any modifications of the present invention in various equivalent forms by those skilled in the art will fall within the scope defined by the appended claims.

[0022] The following is a technical route for preparing dihydrofuran-containing compounds using α-haloesters according to the present invention:

[0023] Step 1, synthesis of olefins: First, add solid Ph3PCH3Br (20 mmol, 2.0 equiv) and potassium tert-butoxide to a dry reaction flask. t Buok (20 mmol, 2.0 equiv) was prepared, and then protected with N2 through three gas exchanges using a double-row tube. Following this, 50 mL of ultra-dry THF (tetrahydrofuran) was added under N2 protection, and the temperature was lowered to 0 °C for 30 min, during which the solution turned bright yellow. Then, at 0 °C, a THF solution of the corresponding ketone (10 mmol, 1.0 equiv) was slowly added dropwise through a constant-pressure dropping funnel, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the reaction was quenched with 100 mL of H2O, extracted with ethyl acetate (AcOEt) (3 × 50 mL), dried over anhydrous Na2SO4, concentrated under vacuum, and the residue was column-passed with petroleum ether to obtain the olefin product.

[0024] The second step is the synthesis of α-haloesters:

[0025] Under a nitrogen atmosphere, NaH (0.7 g, 28 mmol, 82. equiv) and 20 mL of toluene were added to a dry 100 mL round-bottom flask. After heating to 110 °C, dimethyl carbonate (DMC) (2.4 mL, 20 mmol, 2.0 equiv) was added and refluxed with stirring for 3 minutes. Then, the corresponding ketone (10 mol, 1 equiv) was slowly added to the reaction mixture. The reaction mixture was allowed to react for another 2 hours. The reaction progress was monitored by TLC. After the reaction was complete, 2 mL of acetic acid was added, resulting in a paste. The reaction mixture was quenched with saturated NH4Cl solution, extracted three times with ethyl acetate (EtOAc) (3 × 20 mL), and the combined organic layers were dried over anhydrous Na2SO4. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 20:1) to obtain the corresponding methyl 3-oxo-3-phenylpropionate compounds, which were then proceeded to the next step.

[0026] Under a nitrogen atmosphere, the corresponding methyl 3-oxo-3-phenylpropionate compound (10 mmol, 1 equiv) and 20 mL of dichloroethane (DCE) were added to a dry 100 mL round-bottom flask. The mixture was stirred at room temperature for 15 min, heated to 80 °C, and sulfonyl chloride was slowly added over 2 hours. The mixture was refluxed, and after the reaction was complete, it was quenched with ice water. The mixture was extracted three times with EtOAc (3 × 20 mL), and the combined organic layers were dried with anhydrous Na2SO4. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 20:1) to obtain the corresponding methyl 2-chloro-3-oxo-3-phenylpropionate compound.

[0027] The third step is the synthesis of dihydrofuran compounds:

[0028] KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1,1-diphenylethylene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the reaction tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to obtain the pure desired product.

[0029] Example 1

[0030] Taking the preparation of 2,5-diphenyl-5-(o-tolyl)-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-methyl-2-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure 2,5-diphenyl-5-(o-tolyl)-4,5-dihydrofuran-3-carboxylate with a yield of 66%. The structural characterization data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.8, 1.9 Hz, 2H), 7.68 – 7.61 (m, 1H), 7.33 (d, J = 7.6 Hz, 3H), 7.26 – 7.13 (m, 7H), 7.11 (s, 1H), 3.89(d, J = 15.5 Hz, 1H), 3.64 (d, J = 15.5 Hz, 1H), 3.61 (s, 3H), 2.01 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.37, 163.20, 143.54, 142.40, 135.42,132.17, 130.50, 129.81, 129.48, 128.43, 127.89, 127.88, 127.73, 126.12,125.65, 101.87, 91.27, 51.14, 44.62, 21.37; Exact Mass ESI-MS: calculated m / z for [C 25 H 22 O3H] + : 371.1642, found:371.1640.

[0031] Example 2

[0032] Taking the preparation of methyl 5-(2-chlorophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-chloro-2-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5-(2-chlorophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 57%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.80 – 7.75 (m, 3H), 7.35 – 7.27 (m, 7H), 7.25 (d, J = 7.1 Hz, 4H), 4.20 (d, J = 16.3 Hz, 1H), 3.65 (s, 1H), 3.63 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 165.27, 162.58, 142.25, 142.07, 131.67,131.19, 130.52, 129.65, 129.40, 129.12, 128.33, 128.16, 127.73, 127.39,126.73, 126.52, 102.59, 90.33, 51.19, 43.97; Exact Mass ESI-MS: calculated m / z for [C 24 H 19 ClO3H] + : 391.1095, found:391.1093.

[0033] Example 3

[0034] Taking the preparation of methyl 5-(2-bromophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-bromo-2-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5-(2-bromophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 55%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 1.4 Hz, 2H), 6.55 – 6.48 (m,12H), 3.48 (d, J = 16.3 Hz, 2H), 2.85 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.24, 162.50, 143.74, 141.90, 134.72,130.51, 129.62, 129.39, 129.28, 128.33, 128.15, 127.75, 127.71, 127.25,126.77, 121.27, 102.53, 91.11, 51.14, 44.19; Exact Mass ESI-MS: calculated m / z for [C 24 H 19 BrO3H] + : 435.0590, found:435.0587.

[0035] Example 4

[0036] Taking the preparation of methyl 2,5-diphenyl-5-(m-tolyl)-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-methyl-3-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 2,5-diphenyl-5-(m-tolyl)-4,5-dihydrofuran-3-carboxylate with a yield of 63%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.90 – 7.78 (m, 2H), 7.41 – 7.33 (m, 5H), 7.26 (t, J = 7.5 Hz, 2H), 7.22 – 7.15 (m, 4H), 7.00 (d, J = 7.1 Hz, 1H), 3.76(d, J = 1.6 Hz, 2H), 3.58 (s, 3H), 2.26 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.39, 163.76, 145.26, 145.04, 138.06, 130.51, 129.87, 129.44, 128.39, 128.35, 128.29, 127.76, 127.53, 126.36,125.67, 122.80, 101.81, 90.95, 51.11, 45.64, 21.66; Exact Mass ESI-MS: calculated m / z for [C 25 H22 O3H] + : 371.1642, found:371.1640.

[0037] Example 5

[0038] Taking the preparation of methyl 5-(3-bromophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-bromo-3-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5-(3-bromophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 56%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.07 – 7.01 (m, 2H), 6.74 (s, 1H), 6.59 –6.45 (m, 9H), 6.43 – 6.32 (m, 2H), 2.94 (q, J = 15.3 Hz, 2H), 2.79 (d, J =0.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.15, 163.51, 147.47, 144.36, 130.72,130.03, 129.53, 129.44, 128.84, 128.58, 127.83, 125.60, 124.36, 122.66,101.84, 90.22, 51.21, 45.53; Exact Mass ESI-MS: calculated m / z for [C 24 H 19 BrO3H] + : 435.0590, found:435.0588.

[0039] Example 6

[0040] Taking the preparation of methyl 5-(4-bromophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-bromo-4-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5-(4-bromophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 53%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 5.9 Hz, 2H), 6.60 – 6.39 (m,12H), 2.93 (q, J = 15.4 Hz, 2H), 2.78 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.17, 163.54, 144.48, 144.21, 131.54,130.66, 129.59, 129.39, 128.54, 127.83, 127.81, 127.51, 125.61, 121.69,101.85, 90.44, 51.14, 45.51;

[0041] Exact Mass ESI-MS: calculated m / z for [C 24 H 19 BrO3H] + : 435.0590, found:435.0588.

[0042] Example 7

[0043] Taking the preparation of methyl 5-(4-chlorophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-chloro-4-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5-(4-chlorophenyl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 58%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.0 Hz, 2H), 6.63 – 6.40 (m,12H), 3.01 – 2.90 (m, 2H), 2.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.19, 163.55, 144.57, 143.66, 133.53,130.65, 129.60, 129.39, 128.57, 128.53, 127.81, 127.19, 125.61, 101.84,90.41, 51.14, 45.56; Exact Mass ESI-MS: calculated m / z for [C 24 H 19 ClO3H] + : 391.1095, found:391.1091.

[0044] Example 8

[0045] Taking the preparation of methyl 2,5-diphenyl-5-(p-tolyl)-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1-methyl-4-(1-phenylvinyl)benzene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 2,5-diphenyl-5-(p-tolyl)-4,5-dihydrofuran-3-carboxylate in 63% yield. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 7.7 Hz, 2H), 6.66 – 6.27 (m,12H), 2.98 (s, 2H), 2.81 (s, 3H), 1.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.40, 163.79, 145.34, 142.16, 137.36,130.51, 129.90, 129.45, 129.08, 128.39, 127.75, 127.51, 125.71, 125.67,101.81, 90.96, 51.06, 45.66, 21.04; Exact Mass ESI-MS: calculated m / z for[C 25 H 22 O3H] + : 371.1642, found: 371.1641.

[0046] Example 9

[0047] Taking the preparation of methyl 5-(naphthyl-2-yl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 2-(1-styryl)naphthalene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5-(naphthyl-2-yl)-2,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 61%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.70 (d, J = 7.9 Hz, 2H), 6.54 (d, J = 8.0Hz, 2H), 6.30 – 6.02 (m, 13H), 2.72 – 2.66 (m, 2H), 2.40 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.37, 163.80, 144.93, 142.15, 133.81,132.88, 130.60, 129.49, 128.83, 128.48, 127.82, 127.57, 126.39, 125.88,124.10, 101.93, 91.13, 51.12, 45.40; Exact Mass ESI-MS: calculated m / z for[C 28 H 22 O3H] + : 407.1642, found: 407.1638.

[0048] Example 10

[0049] Taking the preparation of methyl 2,5,5-triphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube assembly, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to obtain pure methyl 2,5,5-triphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 71%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.9 Hz, 2H), 7.53 – 7.44 (m,7H), 7.39 – 7.33 (m, 4H), 7.30 (d, J = 7.2 Hz, 2H), 3.87 (s, 2H), 3.68 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 165.36, 163.74, 145.11, 130.55, 129.81,129.44, 128.42, 127.77, 127.59, 125.70, 101.81, 90.92, 51.10, 45.66; Exact Mass ESI-MS: calculated m / z for [C 24 H 20 O3H] + : 357.1485, found:357.1483.

[0050] Example 11

[0051] Taking the preparation of methyl 5,5-diphenyl-2-(o-tolyl)-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube assembly, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-(o-tolyl)propionate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5,5-diphenyl-2-(o-tolyl)-4,5-dihydrofuran-3-carboxylate with a yield of 62%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.22 – 5.95 (m, 14H), 2.58 (s, 2H), 2.29 (s,3H), 0.97 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.14, 165.09, 145.11, 137.04,130.59, 130.02, 129.65, 129.36, 128.41, 127.64, 125.82, 125.27, 104.01,92.20, 51.01, 44.50, 19.66; Exact Mass ESI-MS: calculated m / z for [C 25 H 22 O3H] + : 371.1642, found:371.1639.

[0052] Example 12

[0053] Taking the preparation of methyl 2-(2-chlorophenyl)-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-(2-chlorophenyl)-3-oxopropionate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 2-(2-chlorophenyl)-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 54%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.67 – 6.60 (m, 5H), 6.56 – 6.42 (m, 9H), 3.02 (s, 2H), 2.74 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.81, 161.71, 144.85, 133.43, 130.79, 130.46, 129.58, 128.37, 127.69, 126.34, 125.91, 105.29, 92.73, 51.07, 44.80; Exact Mass ESI-MS: calculated m / z for [C 24 H 19 ClO3H] + : 391.1095, found:391.1092.

[0054] Example 13

[0055] Taking the preparation of methyl 2-(3-chlorophenyl)-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-(3-chlorophenyl)-3-oxopropionate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 2-(3-chlorophenyl)-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 51%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.08 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.62– 6.49 (m, 10H), 6.46 – 6.40 (m, 2H), 3.00 (s, 2H), 2.83 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.06, 161.86, 144.84, 133.76, 131.45,130.54, 129.33, 129.07, 128.47, 127.72, 127.70, 125.65, 102.89, 91.17, 51.25,45.64; Exact Mass ESI-MS: calculated m / z for [C 24 H 19 ClO3H] + : 391.1095, found:391.1092.

[0056] Example 14 Taking the preparation of methyl 5,5-diphenyl-2-(m-tolyl)-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxo-3-(m-tolyl)propionate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 5,5-diphenyl-2-(m-tolyl)-4,5-dihydrofuran-3-carboxylate with a yield of 61%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.3 Hz, 2H), 7.49 (d, J = 7.2Hz, 4H), 7.39 – 7.26 (m, 8H), 3.86 (s, 2H), 3.68 (s, 3H), 2.43 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.38, 163.98, 145.15, 137.39, 131.34,129.81, 129.74, 128.41, 127.67, 127.58, 126.68, 125.73, 101.66, 90.87, 51.08,45.72, 21.49; Exact Mass ESI-MS: calculated m / z for [C 25 H 22 O3H] + : 371.1642, found:371.1640.

[0057] Example 15 Taking the preparation of methyl 2-(4-ethylphenyl)-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-(4-ethylphenyl)-3-oxopropionate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the reaction tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to give pure methyl 2-(4-ethylphenyl)-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 60%. The structural characterization data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.41 – 7.36 (m,4H), 7.29 – 7.22 (m, 4H), 7.18 (dd, J = 7.6, 1.9 Hz, 4H), 3.75 (s, 2H), 3.58(s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.46, 163.96, 147.13, 145.20, 129.50,128.39, 127.54, 127.31, 127.13, 125.72, 101.17, 90.71, 51.05, 45.71, 28.94,15.34; Exact Mass ESI-MS: calculated m / z for [C 26 H 24 O3H] + : 385.1798, found:385.1796.

[0058] Example 16

[0059] Taking the preparation of methyl 2-methyl-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with the following structural formula as an example, the preparation method is as follows: KHCO3 (60.1 mg, 0.6 mmol) and Zn(OAc)2 (73.4 mg, 0.4 mmol) were added to a dry Schlenk tube (10 mL) containing a magnetic dome. The tube was connected to a double-row tube, evacuated, and backfilled with nitrogen three times. Then, DCE (2 mL), methyl 2-chloro-3-oxobutyrate (0.6 mmol), 1,1-stilbene (0.2 mmol), and N-methylindole (10 mol%) were added under a nitrogen atmosphere. Finally, the reaction mixture in the sealed tube was placed in a water bath, with the reaction tube positioned 1–2 cm away from a 45 W 460 nm blue LED, and stirred at room temperature (35°C) for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 1.0 mL H2O, extracted three times with EtOAc, and then concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography (PE / EtOAc = 50:1) to obtain pure methyl 2-methyl-5,5-diphenyl-4,5-dihydrofuran-3-carboxylate with a yield of 61%. The structural characterization data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.16 (m, 10H), 3.62 (s, 3H), 3.53 (s,2H), 2.28 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 166.65, 166.19, 145.10, 128.34,127.54, 125.65, 101.51, 91.63, 50.89, 44.07, 14.23; Exact Mass ESI-MS: calculated m / z for [C 19 H 18 O3H] + : 295.1329, found:295.1325.

[0060] Comparative Examples Entry Variation from standard conditions compared to Example 10 Yield 1 No deviation 71% 2 No light ND 3 No alkali added 19% 4 Without Lewis acid 21% 5 Na2HPO4 in place of KHCO3 59% 6 CsCO3 in place of KHCO3 31% 7 [KF as an alternative to KHCO3] 30% 8 [HCOOK replaces KHCO3] 50% 9 <![CDATA[Replacement of Zn(OAc)2 with ZnCl2]]> trace 10 <![CDATA[Replacement of Zn(OAc)2 with CuCl]]> 42% 11 <![CDATA[Zn(OTf)3 replaces Zn(OAc)2]]> ND 12 THF replaces DCE 50% 13 1,4-dioxane as an alternative to DCE trace 14 DMF replaces DCE trace 15 <![CDATA[CH3CN replaces DCE]]> 48% 16 <![CDATA[KHCO 3 (4 equal parts) Replace KHCO 3 (3 equal parts) 59% 17 <![CDATA[KHCO3 (in two equal parts) replaces KHCO 3 (in three equal parts)]]> 57% 18 <![CDATA[Zn(OAc)2 (3 equal portions) replaces Zn(OAc) 2 (2 equal portions)]]> 62% 19 <![CDATA[Zn(OAc)2 (1 equivalent) replaces Zn(OAc) 2 (2 equivalents)]]> 58%

[0061] w / o = None, ND = Not detected

[0062] Through the experiments described above, the inventors found that no product was observed without blue light irradiation, indicating that light plays a crucial role in the reaction transformation. Furthermore, while the reaction could occur without the addition of KHCO3 or Zn(OAc)2, the yield was significantly reduced, suggesting that both play important roles in the reaction system. The effect of using different types of bases on the reaction was investigated, with KHCO3 showing the best reaction efficiency. The effect of using different types of Lewis acids was also investigated, with Zn(OAc)2 showing the best reaction efficiency. Next, solvent selection was performed, and DCE showed the best reaction efficiency. Finally, the amounts of KHCO3 and Zn(OAc)2 were investigated, and increasing or decreasing the amounts of both led to a decrease in yield.

[0063] The preferred embodiment of this invention uses 1,1-diphenylethylene (0.2 mmol, 1.0 equiv) and methyl 2-chloro-3-oxo-3-phenylpropionate (0.6 mmol, 3.0 equiv) as template substrates to achieve visible light-catalyzed olefin cyclization reactions involving α-haloesters to construct dihydrofuran compounds. Through optimization of reaction conditions, the target product was finally obtained with a separation yield of 71% under nitrogen protection at room temperature, using N-methylindole as the electron donor for the EDA complex, KHCO3 as the base, Zn(OAc)2 as the Lewis acid, DCE as the solvent, and irradiation with a 45 W 460 nm blue light lamp. This invention provides a one-step method for synthesizing indole-containing 2,2,5,5-tetrasubstituted tetrahydrofurans in a multi-component reaction. This method has the advantages of readily available raw materials, no need for any expensive catalysts, mild conditions, simple operation, good yield, and a wide substrate range.

[0064] The above description is only a partial embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method of utilizing α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: Under blue light catalysis and nitrogen protection, and with the addition of a base, Lewis acid, and solvent, using EDA complexes as electron donors, ... α - Haloesters undergo cyclization reactions with olefins to prepare dihydrofuran compounds.

2. The use of, according to claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The EDA complex is adopted N -Methylindole, N -Ethylindole.

3. The use of, according to claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The α - The halogenated esters are methyl 2-chloro-3-oxo-3-phenylpropionate and methyl 2-chloroacetoacetate.

4. The use of, according to claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The olefin is 1,1-diphenylethylene.

5. The use of claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The base is selected from KHCO3, Na2HPO4, and HCOOK; the Lewis acid is selected from Zn(OAc)2 and CuCl; and the solvent is selected from dichloroethane (DCE), acetonitrile (CH3CN), and tetrahydrofuran (THF).

6. The use of claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The power of the blue light irradiation is 45-50W, and the wavelength is 460-500nm.

7. The use of claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: reactants α - The molar ratio of the halogenated ester to the olefin is 2.5-3.5:

1.

8. The use of claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The molar ratio of the amount of the base, Lewis acid and EDA complex added to the olefin is (2.5-3.5):(1.5-2.5):(0.05-0.15):

1.

9. The use of claim 1 α A method for preparing dihydrofuran-containing compounds from haloesters, characterized in that: The volume ratio of the solvent added to the olefin is 1 mL / mmol.

10. The use of any one of claims 1-9 α A method for preparing dihydrofuran-containing compounds from halogenated esters, characterized in that... Includes the following steps: S1, KHCO3 and zinc acetate Zn(OAc)2 are added to the reaction vessel in proportion, and nitrogen is backfilled after vacuuming; S2, under a nitrogen atmosphere, dichloroethane (DCE) is added as solvent, followed by the addition of methyl 2-chloro-3-oxo-3-phenylpropionate, 1,1-diphenylethylene, and... N 1-Methylindole, mix and stir until homogeneous; S3, place the reaction mixture in a water bath and stir for 12-36 h under 45 W 460 nm blue irradiation catalysis; S4, the reaction mixture was quenched with pure water in the reaction system, then extracted at least once with ethyl acetate (EtOAc), and the crude product was obtained by concentration under reduced pressure; the crude product was then purified by rapid silica gel column chromatography to obtain the purified target product.

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