A method for synthesizing oxidized indole compounds

Abstract

The present invention discloses a method for synthesizing an oxidized indole compound represented by Formula 3, characterized in that the synthesis method comprises the following steps: reacting an N-alkyl-N-phenylmethacrylamide represented by Formula 1 with a cesium-2-oxoacetate compound represented by Formula 2 in a solvent in the presence of an oxidant and under illumination in a nitrogen atmosphere; after completion of the reaction, the reaction mixture is separated and purified to obtain the oxidized indole compound represented by Formula 3; the reaction equation is as follows. The present invention uses N-alkyl-N-phenylmethacrylamide and cesium-2-oxoacetate as reaction substrates, can rapidly react to generate the oxidized indole compound without using a photocatalyst, can increase the yield of the target product, is simple to operate, has mild reaction conditions, and uses low-priced raw materials and solvents throughout the process, which is beneficial for cost control.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, in particular to a method for synthesizing oxidized indole compounds. Background Art

[0002] Oxidole is a fundamental building block of natural products and drug intermediates, exhibiting significant pharmacological and physiological activities. Given its importance, the synthesis of the oxindole skeleton has garnered significant attention from pharmacologists and synthetic chemists. Due to the high atom economy and efficiency of the radical addition / cyclization cascade reaction, the synthesis of oxindoles containing various substituents, as well as various radical addition / cyclization reactions, has been extensively developed using N-alkyl-N-phenylmethacrylamides. For example, perfluoro, acyl, alkyl, sulfonyl, and cyanide radicals undergo radical addition / cyclization reactions with N-alkyl-N-phenylmethacrylamides to afford the corresponding substituted oxindoles. Alkyl-substituted oxindoles are an important branch of the oxindole family.

[0003] Li's group reported a visible-light-induced PPh2Cy / CsI-promoted tandem radical decarboxylation / cyclization of NHPI esters with N-alkyl-N-phenylmethacrylamides [Tetrahedron 117-118(2022)132849]. Zou's group reported a radical alkylation / cyclization reaction of N-alkyl-N-phenylmethacrylamides, in which aryl diazonium salts were used as alkyl radical precursors [J.Org.Chem.2013,78,12202-12206]. Wang and colleagues reported a deborylation arylation reaction of N-alkyl-N-phenylmethacrylamides with boronic acid to provide alkyl-substituted oxidized indoles [Org.Biomol.Chem,2019,17,6612–6619]. However, these reported synthetic methods for alkylated oxidized indoles often suffer from shortcomings such as narrow substrate scope and poor atom efficiency. Given the potential importance of alkylated oxindoles, more efficient synthetic methods remain desirable.

[0004] Therefore, it is necessary to develop a synthetic method with mild reaction conditions, simple operation and high yield. Summary of the Invention

[0005] The present invention aims to provide a method for synthesizing oxidized indole compounds with mild reaction conditions, simple operation, no need for photocatalyst and high yield.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for synthesizing an oxidized indole compound represented by Formula 3, comprising: reacting an N-alkyl-N-phenylmethyl acrylamide represented by Formula 1 with a cesium 2-oxoacetate compound represented by Formula 2 in a solvent in a nitrogen atmosphere in the presence of an oxidant and under light conditions; after completion of the reaction, separating and purifying the reaction mixture to obtain the oxidized indole compound represented by Formula 3;

[0008] The solvent is selected from at least one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP);

[0009] The oxidant is selected from at least one of (NH4)2S2O8, tert-butyl peroxide (TBHP), and K2S2O8;

[0010] The reaction equation is as follows:

[0011]

[0012] Among them, R 1 is C1-C4 alkyl, halogen or C1-C4 alkoxy;

[0013] R 2 is a C1-C4 alkyl group;

[0014] R 3 It is a cyclohexyl group or a cyclohexyl group substituted with a C-C4 alkyl group.

[0015] In the present invention, the C1-C4 alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; the C1-C4 alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0016] Preferably, the oxidant is (NH4)2S2O8 or K2S2O8, more preferably (NH4)2S2O8.

[0017] Preferably, the molar ratio of the N-alkyl-N-phenylmethyl acrylamide to the cesium 2-oxoacetate compound and the oxidant is 1:1-2:2-3, and the optimal molar ratio is 1:2:3.

[0018] Preferably, the light source used for the illumination is a blue LED lamp, a green LED lamp or a white LED lamp, more preferably a green LED lamp, in particular a 7W green LED lamp.

[0019] Preferably, the reaction temperature is 50-70°C, most preferably 60°C, and the reaction is complete as monitored by TLC.

[0020] The present invention is particularly preferred: the solvent is DMSO, the molar ratio of N-alkyl-N-phenylmethyl acrylamide to cesium 2-oxoacetate and the oxidant is 1:2:3, the oxidant is (NH4)2S2O8, the light source is a 7w green LED, and the reaction temperature is 60°C.

[0021] Preferably, the separation and purification steps are as follows: after the reaction is completed as monitored by TLC, water is added to quench the reaction, the resulting mixture is extracted with dichloromethane, the collected organic phase is washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and then purified by column chromatography to obtain an oxidized indole compound. It is further preferred that the column chromatography use a silica column, the eluent is a mixed solvent of petroleum ether and ethyl acetate; it is further preferred that the eluent is V 石油醚 :V 乙酸乙酯 =20:1.

[0022] In the present invention, the raw material N-alkyl-N-phenyl methacrylamide can be obtained by reference to the literature [Org Biomol Chem. 2022, 20(41): 8042-8048.], and the specific method is as follows:

[0023] To a mixture of an aniline derivative (1.0 equiv), Et3N (2.0 equiv), and dichloromethane (DCM), 2-methacryloyl chloride (1.2 equiv) was added portionwise at 0°C, and the resulting mixture was stirred at room temperature until the aniline derivative was completely consumed. The reaction mixture was quenched with water and saturated NaHCO3, then extracted with dichloromethane, and the combined organic phases were dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the N-phenylmethylacrylamide product. The above N-phenylmethylacrylamide (1.0 equiv) was dissolved in anhydrous THF, and then NaH (1.5 equiv) was added portionwise to the solvent at 0°C under an N2 atmosphere. After 30 minutes, CH3I (1.2 equiv) was added dropwise to the solution, and the resulting mixture was stirred at room temperature until the N-phenylmethylacrylamide was completely consumed. The reaction mixture was quenched with water and saturated NH4Cl, extracted with dichloromethane, and the combined organic phases were dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the desired N-methyl-N-phenylmethacrylamide product.

[0024] The reaction equation is as follows:

[0025]

[0026] Where R 1 、R 2 The definition of is the same as that of formula 1.

[0027] In the present invention, the synthesis of the raw material cesium 2-oxoacetate compound can refer to the literature [J.Am.Chem.Soc, 2015, 137, 35, 11270–11273], and the specific method is as follows:

[0028] (1) The corresponding alcohol (1.0 equivalent), CH2Cl2 (DCM), triethylamine (1.2 equivalents) and DMAP (0.1 equivalents) were added to a round-bottom flask, followed by the dropwise addition of methyl 2-chloro-2-oxoacetate (1.2 equivalents); the reaction was stirred at room temperature for 1 hour and then quenched with saturated NH4Cl (aqueous solution); the aqueous phase was extracted with DCM, and the organic extract was dried over Na2SO4 and concentrated; the crude material was purified by flash column chromatography on silica gel (85:15 / hexane:Et2O) to obtain the desired product as a colorless oil; the reaction equation is as follows:

[0029]

[0030] (2) The above-mentioned monoalkyl oxalate (1.0 equivalent) was added to a round-bottom flask, followed by THF. 1N CsOH aqueous solution (1.0 equivalent) was added dropwise to the solution. The mixture was vigorously stirred at room temperature for 5 minutes and then concentrated under reduced pressure to obtain a colorless solid, i.e., cesium 2-oxoacetate. The reaction equation is as follows:

[0031]

[0032] Where R 3 The definition of is the same as that of formula 2.

[0033] Compared with the prior art, the present invention has the following beneficial effects: the present invention uses N-alkyl-N-phenylmethyl acrylamide and cesium 2-oxoacetic acid compounds as reaction substrates, can react quickly to generate oxidized indole compounds without using a photocatalyst, can achieve an improved yield of the target product, and the product yield can reach more than 80%. The operation is simple, the reaction conditions are mild, and the raw materials and solvents used in the entire process are low in price, which is conducive to cost control. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 and Figure 2 They are respectively the hydrogen spectrum and carbon spectrum of 1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one synthesized in Example 1.

[0035] Figure 3 and Figure 4 They are respectively the hydrogen spectrum and carbon spectrum of 1,3,5-trimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one synthesized in Example 2.

[0036] Figure 5and Figure 6 They are respectively the hydrogen spectrum and carbon spectrum of 5-methoxy-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one synthesized in Example 3.

[0037] Figure 7 and Figure 8 They are respectively the hydrogen spectrum and carbon spectrum of 5-fluoro-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one synthesized in Example 4.

[0038] Figure 9 and Figure 10 They are respectively the hydrogen spectrum and carbon spectrum of 5-chloro-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one synthesized in Example 5.

[0039] Figure 11 and Figure 12 They are respectively the hydrogen spectrum and carbon spectrum of 5-bromo-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one synthesized in Example 6. DETAILED DESCRIPTION

[0040] The following is a further clear and complete description of the technical features of the technical solution provided by the present invention in conjunction with specific embodiments. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0041] Example 1: 1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0042] (1) Synthesis of N-alkyl-N-phenylmethacrylamide

[0043] To a mixture of 0.93 g of aniline (10 mmol, 1.0 equivalent) and 2.02 g of Et3N (20.0 mmol, 2.0 equivalent) in dichloromethane (DCM, 30.0 mL), 2-methacryloyl chloride (12.0 mmol, 1.2 equivalent) was added in equal portions at 0°C. The resulting mixture was stirred at room temperature until the aniline was completely consumed. The reaction mixture was quenched with water (3.0 mL) and saturated NaHCO3 (3.0 mL), then extracted with dichloromethane (DCM, 10.0 mL x 3), and the combined organic phases were dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the N-phenylmethylacrylamide product. The above-mentioned N-phenylmethylacrylamide (5.0mmol, 1.0 equivalent) was dissolved in anhydrous THF (20.0mL), and then under N2 atmosphere, NaH (7.5mmol, 1.5 equivalents) was added to the solvent in batches at 0°C. After 30 minutes, CH3I (6.0mmol, 1.2 equivalents) was added dropwise to the solution, and the resulting mixture was stirred at room temperature until the N-phenylmethylacrylamide was completely consumed. The reaction mixture was quenched with water (3.0mL) and saturated NH4Cl (3.0mL) and extracted with dichloromethane (DCM, 10.0mL×3). The combined organic phases were dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 1.31 grams of N-methyl-N-phenylmethylacrylamide in a yield of 75%.

[0044] (2) Synthesis of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate

[0045] A round-bottom flask was charged with 2.28 g of 1-methylcyclohexyl alcohol (20 mmol, 1.0 eq) and CH2Cl2(DCM) (200 mL, 0.1 M). 2.424 g of triethylamine (3.4 mL, 24 mmol, 1.2 eq) and DMAP (250 mg, 2 mmol, 0.1 eq) were added, followed by the slow dropwise addition of 2.94 g of methyl 2-chloro-2-oxoacetate (2.2 mL, 24 mmol, 1.2 eq). The reaction was stirred at room temperature for 1 hour and then quenched with saturated NH4Cl(aq) (100 mL). The organic and aqueous phases were separated, and the aqueous phase was extracted three times with DCM (100 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, and the solvent removed under vacuum. The crude product was purified by flash chromatography on silica gel (85:15 / hexane:Et2O) to yield a colorless oil. The monoalkyl oxalate obtained above (19.5 mmol, 1.0 equivalent) was added to a round-bottom flask, followed by THF (19.5 mL, 1 M). A 1N aqueous solution of CsOH (19.5 mL, 19.5 mmol, 1.0 equivalent) was added dropwise to the solution. The mixture was vigorously stirred at room temperature for 5 minutes and concentrated under reduced pressure to obtain 4.8 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate as a colorless solid in a 74% yield.

[0046] (3) Synthesis of 1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0047] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.0318 g of N-methyl-N-phenylmethylacrylamide 1a (0.2 mmol, 1 equiv), 0.06343 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.4 mmol, 2 equiv), 0.137 g of (NH4)2S2O8 (0.6 mmol, 3 equiv), and DMSO (2 mL). The reaction mixture was irradiated with a green LED (7 W) at 60°C under a nitrogen atmosphere until the starting material was completely consumed. The reaction mixture was then quenched with water. The aqueous and organic phases were separated, and the aqueous phase was extracted three times with CHCl2. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.05 g of 1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in a yield of 91%.

[0048] Product characterization data: 1H NMR (400MHz, CDCl3) δ7.27–7.23(m,1H),7.20(d,J=7.3Hz,1H),7.02(dd,J=10.9,4.1Hz,1H),6.84(d,J=7.8Hz,1H),3.22 (s,3H),2.10(d,J=14.5Hz,1H),1.91(d,J=14.5Hz,1H),1.39–1.31(m,2H),1.29(s,3H),1.26–0.82(m,8H),0.49(s,3H). 13 C NMR (101MHz, CDCl3) δ181.4,142.8,134.6,127.6,123.9,122.0,108.1,50.8,47.2,39.3,39.1,34.3,28.8,26.4,26.3,24.2,22.0,21.9.

[0049] Example 2: 1,3,5-trimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0050] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.0378 g of N-methyl-N-(p-tolyl)methacrylamide 1b (0.2 mmol, 1 eq), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.4 mmol, 2 eq), 0.137 g of (NH4)2S2O8 (0.6 mmol, 3 eq), and DMSO (2 mL). The reaction mixture was irradiated with a green LED (7 W) at 60°C under a nitrogen atmosphere until the starting material was completely consumed. The reaction mixture was quenched with water. The organic and aqueous phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.051 g of 1,3,5-trimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in an 89% yield.

[0051] Product characterization data: 1 H NMR (400MHz, CDCl3) δ7.09–7.05(m,1H),7.04(s,1H),6.74(d,J=7.8Hz,1H),3.21(s,3H),2.35(s,3H),2.09(d,J=11. 8Hz,1H),1.92(d,J=14.5Hz,1H),1.46–1.32(m,3H),1.29(s,3H),1.27–1.13(m,4H),1.06–0.86(m,3H),0.52(s,3H).13 C NMR (101MHz, CDCl3) δ181.4,140.5,134.7,131.5,127.8,124.7,107.8,50.7,47.2,39.2,39.1,34.3,28.8,26.4,26.3,24.3,22.0,21.9,21.3.

[0052] Example 3: 5-methoxy-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0053] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.041 g of N-(4-methoxyphenyl)-N-methylmethacrylamide 1c (0.2 mmol, 1 equiv), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.4 mmol, 2 equiv), 0.137 g of (NH₄)₂S₂O₂ (0.6 mmol, 3 equiv), and DMSO (2 mL). The reaction mixture was irradiated with a green LED (7 W) at 60°C under a nitrogen atmosphere until the starting material was completely consumed. The reaction mixture was quenched with water, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with CH₂Cl₂. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.052 g of 5-methoxy-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in an 87% yield.

[0054] Product characterization data: 1 H NMR (400MHz, CDCl3) δ6.85(d,J=2.3Hz,1H),6.81(dd,J=8.4,2.4Hz,1H),6.76(d,J=8.4Hz,1H),3.82(s,3H),3.22(s,3H),2.11(d,J=14.5H z,1H),1.91(d,J=14.5Hz,1H),1.43–1.33(m,3H),1.30(s,3H),1.20(m,4H),1.03(dd,J=12.6,5.7Hz,1H),0.97–0.88(m,2H),0.54(s,3H). 13 C NMR (101MHz, CDCl3) δ181.0,155.7,136.5,136.1,111.8,111.5,108.3,56.0,50.4,47.6,39.3,39.1,34.3,28.8,26.5,26.3,24.3,22.0,22.0.

[0055] Example 4: 5-Fluoro-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0056] A schlenk tube (25 mL) was equipped with a magnetic stirrer and charged with 0.0386 g of N-(4-fluorophenyl)-N-methylmethacrylamide 1d (0.2 mmol, 1 eq), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.4 mmol, 2 eq), 0.137 g of (NH4)2S2O8 (0.6 mmol, 3 eq), and DMSO (2 mL). The reaction mixture was irradiated with a green LED (7 W) at 60°C under nitrogen until the starting material was completely consumed. The mixture was quenched with water. The organic and aqueous phases were separated, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.053 g of 5-fluoro-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in a yield of 92%.

[0057] Product characterization data: 1 H NMR(400MHz, CDCl3)δ7.03–6.94(m,2H),6.77(dd,J=9.1,4.2Hz,1H),3.23(s,3H),2.14(d,J=14.5Hz,1H), 1.89(d,J=14.5Hz,1H),1.45–1.33(m,3H),1.30(s,3H),1.28–1.13(m,4H),1.07–0.89(m,3H),0.53(s,3H). 13 C NMR (101MHz, CDCl3) δ180.9, 159.2 (d, J = 239.8Hz), 138.7 (d, J = 1.4Hz), 136.5 (d, J = 7.9Hz), 113.8 (d, J = 23.4H z), 111.9 (d, J = 24.3Hz), 108.5 (d, J = 8.2Hz), 50.9, 47.7, 39.4, 39.0, 34.3, 28.7, 26.5, 26.3, 24.2, 22.0, 21.9.

[0058] Example 5: 5-chloro-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0059] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.0418 g of N-(4-chlorophenyl)-N-methylmethacrylamide 1e (0.2 mmol, 1 equiv), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.4 mmol, 2 equiv), 0.137 g of (NH4)2S2O8 (0.6 mmol, 3 equiv), and DMSO (2 mL). The reaction mixture was irradiated with a green LED (7 W) at 60°C under a nitrogen atmosphere until the starting material was completely consumed. The mixture was quenched with water, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.053 g of 5-chloro-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in a yield of 91%.

[0060] Product characterization data: 1 H NMR (400MHz, CDCl3) δ7.24(dd,J=8.2,1.7Hz,1H),7.19(d,J=2.0Hz,1H),6.77(d,J=8.2Hz,1H),3.22(s,3H),2.12(d,J=14.5Hz,1 H),1.89(d,J=14.5Hz,1H),1.48–1.32(m,3H),1.30(s,3H),1.26–1.11(m,4H),1.06–0.98(m,1H),0.96–0.87(m,2H),0.52(s,3H). 13 C NMR (101MHz, CDCl3) δ180.7,141.4,136.5,127.5,124.3,109.0,50.8,47.4,39.4,39.0,34.3,28.6,26.5,26.3,24.3,22.0,21.9.

[0061] Example 6: 5-Bromo-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one

[0062] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.051 g of N-(4-bromophenyl)-N-methylmethacrylamide 1 (0.2 mmol, 1 equiv), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate 2 (0.4 mmol, 2 equiv), 0.137 g of (NH4)2S2O8 (0.6 mmol, 3 equiv), and DMSO (2 mL). The reaction mixture was irradiated with a 7 W LED at 60°C under a nitrogen atmosphere until the starting material was completely consumed. The mixture was quenched with water, and the organic and aqueous phases were separated. The aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.063 g of 5-bromo-1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in an 89% yield.

[0063] Product characterization data: 1 H NMR (400MHz, CDCl3) δ7.16–7.13(m,1H),7.11(t,J=5.4Hz,1H),6.82–6.76(m,1H),3.20(d,J=7.4Hz,3H ),2.41(d,J=14.5Hz,1H),1.92(dd,J=18.1,8.7Hz,1H),1.45(s,3H),1.42–1.02(m,10H),0.54(s,3H). 13 CNMR (101MHz, CDCl3) δ180.6,144.9,132.7,129.1,126.9,120.1,107.2,49.3,49.0,38.7,38.3,34.4,26.5,26.3,24.6,22.4,21.5,22.0.

[0064] Example 7

[0065] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.0318 g of N-methyl-N-phenylmethylacrylamide 1a (0.2 mmol, 1 equiv), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.2 mmol, 1 equiv), 0.1080 g of K2S2O8 (0.4 mmol, 2 equiv), and DMSO (2 mL). The reaction mixture was irradiated with a blue LED (7 W) at 50°C under nitrogen until the starting material was completely consumed. The reaction mixture was then quenched with water. The aqueous and organic phases were separated, and the aqueous phase was extracted three times with CHCl2. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.028 g of 1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one in a yield of 51%.

[0066] Examples 8-10

[0067] Example 7 was repeated, with the only difference being that the solvent was changed to NMP (Example 7), DMF (Example 8), and THF (Example 9). The reaction results are shown in Table 1:

[0068] Table 1

[0069]

[0070] Standard conditions: oxidant (K2S2O8), feed ratio (1:1:2), temperature (50°C), 7W blue light.

[0071] Example 11

[0072] A 25 mL Schlenk tube equipped with a magnetic stirrer was charged with 0.0318 g of N-methyl-N-phenylmethylacrylamide 1a (0.2 mmol, 1 equiv), 0.0634 g of cesium 2-((1-methylcyclohexyl)oxy)-2-oxoacetate (0.2 mmol, 1 equiv), the oxidant (NH₄)₂S₂O₂ (0.4 mmol, 2 equiv), and DMSO (2 mL). The reaction mixture was irradiated with a blue LED (7 W) at 50°C under nitrogen until the starting material was completely consumed. The reaction mixture was then quenched with water. The aqueous and organic phases were separated, and the aqueous phase was extracted three times with CHCl₂. The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the solvent removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate 20:1 as eluent) to give 0.028 g of 1,3-dimethyl-3-((1-methylcyclohexyl)methyl)indolin-2-one.

[0073] Examples 12-13

[0074] Example 11 was repeated, with the only difference being that the oxidant was changed to K2S2O8 (Example 12) or TBHP (Example 13). The reaction results are shown in Table 2:

[0075] Table 2

[0076]

[0077] Standard conditions: solvent (DMSO), feed ratio (1:1:2), temperature (50°C), 7W blue light.

[0078] Examples 14-16

[0079] Example 11 was repeated, with the only difference being that the molar ratio of the N-alkyl-N-phenylmethyl acrylamide, the cesium 2-oxoacetate compound, and the oxidant was changed to 1:1:3 (Example 14), 1:2:2 (Example 15), and 1:2:3 (Example 16). The reaction results are shown in Table 3:

[0080] Table 3

[0081]

[0082] Standard conditions: solvent (DMSO), oxidant (NH4)2S2O8), temperature (50℃), 7W blue light.

[0083] Examples 17-18

[0084] Example 16 was repeated, with the only difference being that the light source was changed to a green LED lamp (Example 17) or a 7W white LED lamp (Example 18). The reaction results are shown in Table 4:

[0085] Table 4

[0086]

[0087] Standard conditions: solvent (DMSO), feed ratio (1:2:3), oxidant (NH4)2S2O8), temperature (50°C).

[0088] Example 19

[0089] Example 17 was repeated, with the only difference being that the reaction temperature was changed to 50° C. (Example 19) and 70° C. (Example 20). The reaction results are shown in Table 5:

[0090] Table 5

[0091]

[0092]

[0093] Standard conditions: solvent (DMSO), feed ratio (1:2:3), oxidant (NH4)2S2O8, 7w green light.

Claims

1. A method for synthesizing an oxidized indole compound represented by formula 3, characterized in that: The synthesis method comprises the following steps: in a nitrogen atmosphere, reacting the N-alkyl-N-phenylmethyl acrylamide represented by Formula 1 with the cesium 2-oxoacetate compound represented by Formula 2 in a solvent in the presence of an oxidant and under light conditions; after the reaction is completed, the reaction mixture is separated and purified to obtain the oxidized indole compound represented by Formula 3; The solvent is selected from dimethyl sulfoxide; The oxidant is selected from at least one of (NH4)2S2O8 and K2S2O8; The reaction equation is as follows: Among them, R 1 is C1-C4 alkyl, halogen or C1-C4 alkoxy; R 2 is a C1-C4 alkyl group; R 3 is a cyclohexyl group or a cyclohexyl group substituted by a C4 alkyl group; or the cesium 2-oxoacetate compound represented by formula 2 is 2-((1-methylcyclohexyl)oxy)-cesium 2-oxoacetate.

2. The synthesis method according to claim 1, wherein: The molar ratio of the N-alkyl-N-phenylmethyl acrylamide, the cesium 2-oxoacetate compound and the oxidant is 1:1-2:2-3.

3. The synthesis method according to claim 2, wherein: The molar ratio of the N-alkyl-N-phenylmethyl acrylamide, the cesium 2-oxoacetate compound and the oxidant is 1:2:

3.

4. The synthesis method according to claim 1, wherein: The light source used for the illumination is a blue LED lamp, a green LED lamp or a white LED lamp.

5. The synthesis method according to claim 1, wherein: The reaction temperature was 50-70°C and the reaction was complete as monitored by TLC.

6. The synthesis method according to claim 5, wherein: The reaction temperature was 60°C.

7. The synthesis method according to claim 1, wherein: The solvent is dimethyl sulfoxide, the molar ratio of N-alkyl-N-phenylmethyl acrylamide to cesium 2-oxoacetate and the oxidant is 1:2:3, the oxidant is (NH4)2S2O8, the light source is a 7W green LED, and the reaction temperature is 60°C.

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