A method for photocatalytic synthesis of indole benzyl sulfone compounds

Abstract

The present invention belongs to the field of organic chemical synthesis, and relates to a method for photocatalytic synthesis of indole benzyl sulfone compounds. An aryl halide 1 is mixed with a sodium sulfinate compound 2, a photosensitizer, a base, 2,6-dimethyl-3,5-diethylcarboester-1,4-dihydropyridine, and a solvent and placed in a reactor, and a photoreaction is carried out under the protection of an inert gas and the irradiation of an LED lamp to obtain an indole benzyl sulfone compound 3. Compared with the prior art, the photocatalytic synthesis method of the present invention is green and environmentally friendly, does not require high temperature conditions, has mild reaction conditions, does not require the use of a strong oxidant, is easy to operate, has a high yield, and is more green and safe.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis and relates to a method for photocatalytically synthesizing indole benzyl sulfone compounds. Background Art

[0002] As an important biologically active group, the indole ring structural unit is widely present in natural product molecules and drug molecules, and exhibits excellent physiological activities in anti-tumor, anti-viral, anti-bacterial, anti-inflammatory, antioxidant and protective effects on the cardiovascular system. Many natural active compounds or active drug intermediates have indole mother core structures, such as Panobinostat Lactate for the treatment of multiple myeloma, Ramosetron Hydrochloride for the treatment of chemotherapy-induced nausea and vomiting, and Etodolac for the treatment of osteoarthritis and rheumatoid arthritis.

[0003] Early literature reported that transition metal-catalyzed coupling cyclization reactions generate indole skeleton structures, but these reactions usually require toxic reagents, stoichiometric strong oxidants, or harsh reaction conditions. Therefore, it is of great significance to explore an efficient and green method to synthesize indole derivatives. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for photocatalytic synthesis of indole benzyl sulfone compounds in view of the deficiencies in the prior art. The method has mild reaction conditions, and the raw material compound 1 (i.e., aromatic halide) is easily available, and no strong oxidant is required. The aromatic halide raw material is intramolecularly dehalogenated and cyclized to synthesize indole derivatives, and the product yield is high and the substrate expansion range is wide.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0006] The present invention discloses a method for photocatalytically synthesizing indole benzyl sulfone compounds, comprising mixing a compound 1 with a sodium sulfinate compound 2, a photosensitizer, a base, 2,6-dimethyl-3,5-diethylcarboester-1,4-dihydropyridine and a solvent, placing the mixture in a reactor, and performing a photoreaction under the protection of an inert gas and the irradiation of an LED lamp to obtain an indole benzyl sulfone compound 3;

[0007]

[0008] in,

[0009] The structural formulas of the compound 1, the sodium sulfinate compound 2, and the indole benzyl sulfone compound 3 are shown in Formula 1, Formula 2, and Formula 3, respectively:

[0010]

[0011] in,

[0012] R1 is selected from fluorine, chlorine, bromine, methyl, methoxy, cyano or trifluoromethyl;

[0013] n represents an integer from 0 to 4;

[0014] R2 is selected from substituted or unsubstituted benzenesulfonyl, methyl, n-octyl, tert-butyloxycarbonyl, acetyl, or substituted or unsubstituted benzyl; wherein the substitution is selected from substitution by alkyl or halogen;

[0015] R is selected from phenyl, (4-methyl)phenyl, (4-methoxy)phenyl, (4-tert-butyl)phenyl, (4-trifluoromethyl)phenyl, (4-fluoro)phenyl, (4-bromo)phenyl, (4-chloro)phenyl, (m-bromo)phenyl, (o-chloro)phenyl, methyl, ethyl or thienyl.

[0016] Wherein, the 2,6-dimethyl-3,5-diethylcarbohydrate-1,4-dihydropyridine is abbreviated as HEH.

[0017] The substitution position of R1 is not limited.

[0018] Wherein, the sodium sulfinate compound 2 is selected from any one of the following:

[0019]

[0020] In some embodiments, preferably:

[0021] R1 is selected from fluorine, chlorine or methoxy;

[0022] n represents an integer from 0 to 2;

[0023] R2 is selected from p-toluenesulfonyl, methyl, tert-butyloxycarbonyl, benzyl or (2-fluoro)benzyl;

[0024] R is selected from (4-methyl)phenyl, (4-methoxy)phenyl, ethyl or thienyl.

[0025] In some embodiments, the photosensitizer is terpyridyl ruthenium chloride hexahydrate, eosin Y disodium salt, tris(2-phenylpyridine)iridium or 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile.

[0026] In some embodiments, preferably, the photosensitizer is terpyridyl ruthenium chloride hexahydrate, eosin Y disodium salt or tris(2-phenylpyridine)iridium.

[0027] In some embodiments, further preferably, the photosensitizer is terpyridyl ruthenium chloride hexahydrate; wherein the abbreviation of terpyridyl ruthenium chloride hexahydrate is Ru(bpy)3Cl2·6H2O.

[0028] In some embodiments, the base is cesium carbonate, potassium carbonate, sodium bicarbonate, lithium carbonate, triethylamine, or N,N-diisopropylethylamine.

[0029] In some embodiments, preferably, the base is cesium carbonate, potassium carbonate, sodium bicarbonate or lithium carbonate.

[0030] In some embodiments, further preferably, the base is cesium carbonate.

[0031] In some embodiments, the solvent is dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide.

[0032] In some embodiments, preferably, the solvent is dimethyl sulfoxide.

[0033] There is no restriction on the amount of the solvent used, as long as it can dissolve the raw materials in the reaction system and have a moderate viscosity.

[0034] In some embodiments, the molar ratio of the compound 1 to the sodium sulfinate compound 2, the photosensitizer, the base, and 2,6-dimethyl-3,5-diethylester-1,4-dihydropyridine is 1:(1.5-3):(0.015-0.05):(1-2):(0.2-0.8).

[0035] In some embodiments, preferably, the molar ratio of the compound 1 to the sodium sulfinate compound 2, the photosensitizer, the base, and 2,6-dimethyl-3,5-diethylester-1,4-dihydropyridine is 1:2:0.03:1.5:0.4.

[0036] In some embodiments, the inert gas is nitrogen.

[0037] In some embodiments, the LED lamp is located outside the reactor, and the illumination range of the LED lamp covers the reactor.

[0038] In some embodiments, preferably, the LED lamp located outside the reactor has blue light with a wavelength of 450nm to 460nm and a power of 24 to 30W.

[0039] In some embodiments, the photoreaction has a reaction temperature of room temperature and a reaction time of 8 to 16 hours.

[0040] In some embodiments, preferably, the photoreaction has a reaction temperature of room temperature and a reaction time of 12 hours.

[0041] Beneficial effects:

[0042] (1) Compared with the prior art (Fuwa, Haruhiko; Sasaki, Makoto, et al., A strategy for the synthesis of 2,3-disubstituted indoles starting from N-(o-halophenyl)allenamides. Organic & Biomolecular Chemistry, 2007, 5, 14, 2214-2218.), the photocatalytic synthesis method of the present invention is green and environmentally friendly, does not require high temperature conditions, has mild reaction conditions, does not require the use of strong oxidants, is easy to operate, has a high yield, and is more green and safe.

[0043] (2) The prior art (Y WU, J CHEN, L LI, et al. Copper-mediated decarboxylativesulfonylation of arylacetic acids with sodium sulfinates [J]. Organic Letters, 2020, 22 (18): 7164-7168.) has recorded that the indole benzyl sulfone compound 3ha has good cytotoxicity to HCT116 when R1 = H, R2 = Bn, and R = (4-methyl) phenyl. The compound 3ga (R1 = H, R2 = (2-F) benzyl, R = (4-methyl) phenyl) prepared in the present application successfully introduced a fluorine atom at the 2-position of the benzyl group, and the compound 3ga has higher potential drug activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] 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.

[0045] Figure 1 1 is an assembly diagram of the device used in the embodiment of the present invention.

[0046] Figure 2 is the compound 3aa in Example 1 of the present invention 1 H NMR spectrum.

[0047] Figure 3 is the compound 3aa in Example 1 of the present invention 13 C NMR spectrum.

[0048] Figure 4 is the compound 3ba in Example 7 of the present invention 1 H NMR spectrum.

[0049] Figure 5is the compound 3ba in Example 7 of the present invention 13 C NMR spectrum.

[0050] Figure 6 is the compound 3ca in Example 8 of the present invention 1 H NMR spectrum.

[0051] Figure 7 is the compound 3ca in Example 8 of the present invention 13 C NMR spectrum.

[0052] Figure 8 is the compound 3ca in Example 8 of the present invention 19 F NMR spectrum.

[0053] Fig. 9 is the compound 3da in Example 9 of the present invention 1 H NMR spectrum.

[0054] Fig.10 is the compound 3da in Example 9 of the present invention 13 C NMR spectrum.

[0055] Fig.11 is the compound 3ea in Example 10 of the present invention 1 H NMR spectrum.

[0056] Fig.12 is the compound 3ea in Example 10 of the present invention 13 C NMR spectrum.

[0057] Fig.13 is the compound 3fa in Example 11 of the present invention 1 H NMR spectrum.

[0058] Fig.14 is the compound 3fa in Example 11 of the present invention 13 C NMR spectrum.

[0059] Fig.15 is the compound 3ga in Example 12 of the present invention 1 H NMR spectrum.

[0060] Fig.16 is the compound 3ga in Example 12 of the present invention 13 C NMR spectrum.

[0061] Fig.17 is the compound 3ga in Example 12 of the present invention 19 F NMR spectrum.

[0062] Fig.18is the compound 3ab in Example 13 of the present invention 1 H NMR spectrum.

[0063] Fig.19 is the compound 3ab in Example 13 of the present invention 13 C NMR spectrum.

[0064] Fig. 20 is the compound 3ac in Example 14 of the present invention 1 H NMR spectrum.

[0065] Fig.21 is the compound 3ac in Example 14 of the present invention 13 C NMR spectrum.

[0066] Fig. 22 is the compound 3ad in Example 15 of the present invention 1 H NMR spectrum.

[0067] Fig.23 is the compound 3ad in Example 15 of the present invention 13 C NMR spectrum.

[0068] Fig.24 This is a graph showing the relationship between yield and illumination in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0069] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0070] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0071] The synthesis method of compound 1 used in the examples of the present invention refers to the prior art: Lhermet, R., Ahmad, M., Fressigné, C., Silvi, B., Durandetti, M., & Maddaluno, J. (2014). Carbolithiation of chloro-substituted alkynes: a new access to vinyl carbenoids. Chemistry (Weinheim an der Bergstrasse, Germany), 20 (33), 10249–10254.

[0072] The LED light source, fan, magnetic stirrer, etc. on the periphery of the reactor used in the embodiments of the present invention were purchased from the market and then assembled by ourselves.

[0073] The assembly diagram of the device used in the embodiment of the present invention is as follows Figure 1 As shown, in order to make the illumination range of the LED lamp fully cover the reactor, the LED lamp is located at the annular periphery and upper side of the reactor; among them, the LED lamp located at the annular periphery of the reactor is blue light with a wavelength of 450nm~455nm and a power of 24W; the LED lamp located on the upper side of the reactor is blue light with a wavelength of 450nm~460nm and a power of 30W.

[0074] Example 1

[0075]

[0076] Aryl halide 1a (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3aa with a yield of 77%.

[0077] Compound 3aa 1 H NMR spectrum Figure 2 As shown, 13 C NMR spectrum Figure 3 The specific NMR data are as follows:

[0078] 1 H NMR(400MHz,Chloroform-d)δ7.95(d,J=8.4Hz,1H),7.74(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.40(s,1 H),7.35-7.24(m,4H),7.18(d,J=7.6Hz,1H),7.13(d,J=8.0Hz,2H),4.43(s,2H),2.40(s,3H),2.38(s,3H). 13C NMR(100MHz,Chloroform-d)δ145.32,144.89,134.98,134.68,129.98,129.70,129. 57,128.55,127.27,126.92,125.11,123.53,119.57,113.52,110.09,53.60,21.62.

[0079] Example 2: Screening of photosensitizers

[0080] The experimental method of this embodiment is the same as that of embodiment 1, except that the photosensitizer terpyridine ruthenium chloride hexahydrate is replaced by eosin Y disodium salt or tris(2-phenylpyridine)iridium.

[0081] When the photosensitizer is eosin Y disodium salt, the yield of the final prepared compound 3aa is 13%.

[0082] When the photosensitizer is tris(2-phenylpyridine)iridium, the final yield of compound 3aa is 61%.

[0083] Example 3: Screening of bases

[0084] The experimental method of this embodiment is the same as that of embodiment 1, except that cesium carbonate is replaced by potassium carbonate, sodium bicarbonate or lithium carbonate.

[0085] When the base is potassium carbonate, the yield of the final compound 3aa is 53%.

[0086] When the base is sodium bicarbonate, the yield of the final compound 3aa is 45%.

[0087] When the base is lithium carbonate, the yield of the final compound 3aa is 41%.

[0088] Example 4: Screening of solvents

[0089] The experimental method of this embodiment is the same as that of Embodiment 1, except that dimethyl sulfoxide is replaced by 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethanol, N,N-dimethylformamide or N,N-dimethylacetamide.

[0090] When the solvent is 1,4-dioxane, N-methylpyrrolidone, tetrahydrofuran, dichloromethane or ethanol, the yield of the final compound 3aa is 0.

[0091] When the solvent was N,N-dimethylformamide, the yield of the final compound 3aa was 34%.

[0092] When the solvent was N,N-dimethylacetamide, the yield of the final compound 3aa was 40%.

[0093] Example 5: Necessity of photosensitizer

[0094] The experimental method of this example is the same as that of Example 1, except that no photosensitizer - terpyridine ruthenium chloride hexahydrate is added, and the final yield of the obtained compound 3aa is 0.

[0095] Example 6: Necessity of nitrogen protection

[0096] The experimental method of this example is the same as that of Example 1, except that the reaction system is not protected by nitrogen, and the reaction system is in air atmosphere, and the yield of the final prepared compound 3aa is 0.

[0097] Example 7

[0098]

[0099] Aryl halide 1b (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ba with a yield of 67%.

[0100] Compound 3ba 1 H NMR spectrum Figure 4 As shown, 13 C NMR spectrum Figure 5 The specific NMR data are as follows:

[0101] 1 H NMR(400MHz,Chloroform-d)δ7.80(d,J=8.8Hz,1H),7.68(d,J=8.0Hz,2H),7.40(d,J=8.4Hz,2H),7.33(s,1H),7.23(d,J=8.0Hz,2 H),7.08(d,J=8.0Hz,2H),6.87(dd,J=8.8,2.4Hz,1H),6.63(d,J=2.4Hz,1H),4.38(s,2H),3.70(s,3H),2.36(s,3H),2.35(s,3H).13 C NMR(100MHz,Chloroform-d)δ156.60,145.25,144.91,134.90,134.70,130.74,129.94,129.56 ,129.30,128.61,128.02,126.84,114.57,114.46,110.28,101.49,55.49,53.68,21.60,21.59.

[0102] Example 8

[0103]

[0104] Aryl halide 1c (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), and 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and subjected to photoreaction for 12h under magnetic stirring at room temperature, nitrogen protection, and irradiation with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) and TLC monitoring of the reaction progress. After the reaction of the raw materials was complete, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ca with a yield of 61%.

[0105] Compound 3ca 1 H NMR spectrum Figure 6 As shown, 13 C NMR spectrum Figure 7 As shown, 19 F NMR spectrum Figure 8 The specific NMR data are as follows:

[0106] 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.4Hz,2H),7.65(dd,J=9.6,2.4Hz,1H),7.44(d,J=8.4Hz,2H),7.34 (s,1H),7.31-7.25(m,3H),7.13(d,J=8.0Hz,2H),6.95-6.87(m,1H),4.38(s,2H),2.39(s,3H),2.38(s,3H). 13C NMR (100MHz, Chloroform-d) δ 161.04 (d, J = 241.6Hz), 145.64, 145.01, 134.93, 134.80, 134.66 (d, J = 6.3Hz), 130.12, 129.62, 128.50, 127. 48(d,J=3.9Hz),126.93,126.01,125.99,120.75(d,J=9.9Hz),112.13(d,J=24.2Hz),110.01,100.88(d,J=28.2Hz),53.58,21.65,21.64. 19 F NMR(376MHz,Chloroform-d)δ-115.36.

[0107] Example 9

[0108]

[0109] Aryl halide 1d (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3da with a yield of 40%.

[0110] Compound 3da 1 H NMR spectrum Fig. 9 As shown, 13 C NMR spectrum Fig.10 The specific NMR data are as follows:

[0111] 1H NMR(400MHz,Chloroform-d)δ7.66(s,1H),7.55(d,J=8.4Hz,2H),7.51(d,J=8.0Hz,2H),7.21(d,J=8.4Hz,2H ),7.18(d,J=8.4Hz,2H),7.10(d,J=2.0Hz,1H),7.04(d,J=2.0Hz,1H),4.32(s,2H),2.35(s,3H),2.34(s,3H). 13 C NMR(100MHz,Chloroform-d)δ145.49,145.43,136.19,134.67,134.10,132.88,130.32,129 .92,129.86,129.53,128.63,127.30,127.02,119.64,118.09,107.99,53.47,21.70,21.67.

[0112] Example 10

[0113]

[0114] Aryl halide 1e (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, with magnetic stirring for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ea with a yield of 85%.

[0115] Compound 3ea 1 H NMR spectrum Fig.11 As shown, 13 C NMR spectrum Fig.12 The specific NMR data are as follows:

[0116] 1H NMR (400MHz, Chloroform-d) δ7.57(d,J=8.4Hz,2H),7.27(s,1H),7.21-7.15(m,4H),7.03-6.96(m,2H),4.49(s,2H),3.75(s,3H),2.37(s,3H). 13 C NMR (100MHz, Chloroform-d) δ144.40,136.68,135.65,130.34,129.46,128.60,127.61,121.98,119.80,118.65,109.35,101.15,54.47,32.95,21.57.

[0117] Embodiment 11

[0118]

[0119] Aryl halide 1f (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3fa with a yield of 41%.

[0120] Compound 3fa 1 H NMR spectrum Fig.13 As shown, 13 C NMR spectrum Fig.14 The specific NMR data are as follows:

[0121] 1 H NMR(400MHz,Chloroform-d)δ8.03(d,J=8.4Hz,1H),7.54(d,J=8.0Hz,2H),7.40(s,1H),7.20(d ,J=7.6Hz,1H),7.17-7.12(m,3H),7.04(t,J=7.6Hz,1H),4.36(s,2H),2.32(s,3H),1.58(s,9H). 13C NMR(100MHz,Chloroform-d)δ148.21,143.76,134.31,134.11,128.60,128.34,127 .60,126.23,123.70,121.82,117.86,114.13,106.86,83.19,52.91,27.12,20.56.

[0122] Example 12

[0123]

[0124] 1g (0.2mmol) of aryl halide, sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), and 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ga with a yield of 65%.

[0125] Compound 3ga 1 H NMR spectrum Fig.15 As shown, 13 C NMR spectrum Fig.16 As shown, 19 F NMR spectrum Fig.17 The specific NMR data are as follows:

[0126] 1 H NMR(400MHz,Chloroform-d)δ7.52(d,J=8.4Hz,2H),7.36(d,J=8.0Hz,1H),7.30-7.23(m,2H),7.19-7.15(m,1H),7.13(d,J=8.0Hz ,2H),7.10-7.06(m,1H),7.06-7.00(m,2H),6.99-6.97(m,1H),6.80(td,J=7.6,1.6Hz,1H),5.29(s,2H),4.50(s,2H),2.35(s,3H). 13C NMR(100MHz,Chloroform-d)δ159.25(d,J=245.3Hz),143.31,135.15,134.21,128.64(d,J=8.0Hz),128.48,128.34,127.93(d,J=3.7Hz),127.59,126.7 3,123.40(d,J=3.7Hz),123.03(d,J=14.5Hz),121.37,119.17,118.04,114. 50(d,J=21.1Hz),108.63,101.39,76.06,53.37,42.76(d,J=4.8Hz),20.54. 19 F NMR(376MHz,Chloroform-d)δ-118.23.

[0127] Example 13

[0128]

[0129] Aryl halide 1a (0.2mmol), sodium p-methoxybenzenesulfinate 2b (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ab with a yield of 62%.

[0130] Compound 3ab 1 H NMR spectrum Fig.18 As shown, 13 C NMR spectrum Fig.19 The specific NMR data are as follows:

[0131] 1H NMR(400MHz,Chloroform-d)δ7.95(d,J=8.4Hz,1H),7.74(d,J=8.4Hz,2H),7.46(d,J=9.2Hz,2H),7.41(s,1H),7.34-7 .28(m,2H),7.26(d,J=8.0Hz,2H),7.19-7.14(m,1H),6.75(d,J=8.8Hz,2H),514.42(s,2H),3.83(s,3H),2.37(s,3H). 13 C NMR(100MHz,Chloroform-d)δ163.83,145.36,134.94,134.66,130.69,130.00,129.69,129 .06,127.23,126.92,125.11,123.56,119.60,114.12,113.51,110.34,55.68,53.76,21.62.

[0132] Embodiment 14

[0133]

[0134] Aryl halide 1a (0.2mmol), sodium ethylsulfinate 2c (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ac with a yield of 57%.

[0135] Compound 3ac 1 H NMR spectrum Fig. 20 As shown, 13 C NMR spectrum Fig.21 The specific NMR data are as follows:

[0136] 1H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.4Hz,1H),7.78(s,1H),7.76(d,J=6.0Hz,2H),7.62(d,J=8.0Hz,1H),7.36(t,J=7.6 Hz,1H),7.29(t,J=7.6Hz,1H),7.23(d,J=8.4Hz,2H),4.34(s,2H),2.85(q,J=7.6Hz,2H),2.33(s,3H),1.32(t,J=7.6Hz,3H). 13 CNMR(100MHz,Chloroform-d)δ145.47,134.96,134.83,130.06,129.57,127.2 3,126.92,125.50,123.89,119.74,113.81,109.66,49.48,45.52,21.59,6.41.

[0137] Embodiment 15

[0138]

[0139] Aryl halide 1a (0.2mmol), sodium thienylsulfinate 2d (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), and 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and subjected to photoreaction for 12h under magnetic stirring at room temperature, nitrogen protection, and irradiation with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) and TLC monitoring of the reaction progress. After the reaction of the raw materials was complete, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ad with a yield of 57%.

[0140] Compound 3ad 1 H NMR spectrum Fig. 22 As shown, 13 C NMR spectrum Fig.23 The specific NMR data are as follows:

[0141] 1H NMR(400MHz,Chloroform-d)δ7.96(d,J=8.4Hz,1H),7.74(d,J=8.4Hz,2H),7.54(dd,J=4.8,1.2Hz,1H),7.47(s,1H ),7.35-7.28(m,2H),7.27-7.23(m,3H),7.20-7.15(m,1H),6.92(dd,J=4.8,4.0Hz,1H),4.53(s,2H),2.35(s,3H). 13 C NMR(100MHz,Chloroform-d)δ145.39,138.20,135.03,134.92,134.68,134.58,130.01, 129.66,127.68,127.47,126.97,125.23,123.66,119.32,113.60,109.95,54.77,21.60.

[0142] Example 16

[0143]

[0144] Aryl halide 1h (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), 2mL DMSO were added to a 25mL reaction tube in sequence, replaced with nitrogen three times, and irradiated with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W) at room temperature, stirred magnetically for photoreaction for 12h, and the reaction progress was monitored by TLC. After the raw materials reacted completely, the reaction solution was extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated by vacuum distillation, and purified by column chromatography to obtain a solid product 3ha with a yield of 60%.

[0145] The NMR data of compound 3ha are as follows:

[0146] 1 H NMR(400MHz,Chloroform-d)δ7.52(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,1H),7.30-7.20(m,4H ),7.17-7.08(m,3H),7.07-6.99(m,3H),6.93(s,1H),5.22(s,2H),4.50(s,2H),2.34(s,3H).13 C NMR(100MHz,Chloroform-d)δ144.35,137.01,136.30,135.23,129.59,129.39,128.81, 128.66,127.81,126.81,122.31,120.13,119.03,109.87,102.19,54.46,50.12,21.60.

[0147] Comparative Example 1: Light Control Experiment

[0148] Aryl halide 1a (0.2mmol), sodium p-toluenesulfinate 2a (0.4mmol), terpyridine ruthenium chloride hexahydrate (0.006mmol), cesium carbonate (0.3mmol), HEH (0.08mmol), and 2mL DMSO were added to a 25mL reaction tube in sequence, and nitrogen was replaced three times. At room temperature, nitrogen protection, and irradiation with a blue LED lamp (the blue LED lamp located outside the reactor has a wavelength of 450nm-455nm and a power of 24W; the blue LED lamp located on the upper side of the reactor has a wavelength of 450nm-460nm and a power of 30W), the photoreaction was carried out with magnetic stirring. After 1h of light reaction, the LED lamp was turned off and the reaction was carried out in the dark for 1h. The light was turned on and off alternately, and multiple groups of reactions were carried out in parallel. The reaction solution after the reaction was completed with different light or no light was purified by column chromatography, and the yield of 3aa was calculated. The relationship between the yield and light is shown in Fig.24 The experimental results show that when there is no light irradiating the reaction system, the reaction does not proceed, and light is a necessary condition for the reaction to proceed.

[0149] The present invention provides a method and idea for photocatalytic synthesis of indole benzyl sulfone compounds. 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 regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for photocatalytic synthesis of indole benzyl sulfone compounds, characterized in that: Compound 1 is mixed with sodium sulfinate compound 2, a photosensitizer, a base, 2,6-dimethyl-3,5-diethylcarbothio-1,4-dihydropyridine, and a solvent and placed in a reactor, and a photoreaction is carried out under the protection of an inert gas and the irradiation of an LED light to obtain an indole benzyl sulfone compound 3; in, The structural formulas of the compound 1, the sodium sulfinate compound 2, and the indole benzyl sulfone compound 3 are shown in Formula 1, Formula 2, and Formula 3, respectively: in, R1 is selected from fluorine, chlorine, bromine, methyl, methoxy, cyano or trifluoromethyl; n represents an integer from 0 to 4; R2 is selected from substituted or unsubstituted benzenesulfonyl, methyl, n-octyl, tert-butyloxycarbonyl, acetyl, or substituted or unsubstituted benzyl; wherein the substitution is selected from substitution by alkyl or halogen; R is selected from phenyl, (4-methyl)phenyl, (4-methoxy)phenyl, (4-tert-butyl)phenyl, (4-trifluoromethyl)phenyl, (4-fluoro)phenyl, (4-bromo)phenyl, (4-chloro)phenyl, (m-bromo)phenyl, (o-chloro)phenyl, methyl, ethyl or thienyl; The photosensitizer is terpyridyl ruthenium chloride hexahydrate, eosin Y disodium salt or tris(2-phenylpyridine)iridium; The base is cesium carbonate, potassium carbonate, sodium bicarbonate or lithium carbonate; The solvent is dimethyl sulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide; The light of the LED lamp is blue light, the wavelength is 450nm-460nm, and the power is 24-30W.

2. The method for photocatalytic synthesis of indole benzyl sulfone compounds according to claim 1, characterized in that: R1 is selected from fluorine, chlorine or methoxy; n represents an integer from 0 to 2; R2 is selected from p-toluenesulfonyl, methyl, tert-butyloxycarbonyl, benzyl or (2-fluoro)benzyl; R is selected from (4-methyl)phenyl, (4-methoxy)phenyl, ethyl or thienyl.

3. The method for photocatalytic synthesis of indole benzyl sulfone compounds according to claim 1, characterized in that: The molar ratio of the compound 1 to the sodium sulfinate compound 2, the photosensitizer, the base, and 2,6-dimethyl-3,5-diethylcarboester-1,4-dihydropyridine is 1:(1.5-3):(0.015-0.05):(1-2):(0.2-0.8).

4. The method for photocatalytic synthesis of indole benzyl sulfone compounds according to claim 1, characterized in that: The inert gas is nitrogen.

5. The method for photocatalytic synthesis of indole benzyl sulfone compounds according to claim 1, characterized in that: The LED lamp is located outside the reactor, and the illumination range of the LED lamp covers the reactor.

6. The method for photocatalytic synthesis of indole benzyl sulfone compounds according to claim 1, characterized in that: The photoreaction has a reaction temperature of room temperature and a reaction time of 8 to 16 hours.

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