Benzyl benzoyl or fluoroalkane substituted phenolic compounds, methods of synthesis and use thereof

Abstract

The application discloses a benzyl benzoyl or fluorinated alkane substituted phenol compound and a synthesis method and application thereof, and belongs to the technical field of drug synthesis. The synthesis method comprises the following steps: step one, 0.3mmol of o-aminobenzamide, 0.3mmol of ketone, 10mol% of I2 and 5mL of anhydrous ethanol are added into a 10mL round-bottom flask at one time, stirring is carried out at 80 DEG C for 24h, after the reaction is completed, the reaction liquid is poured into ice water, the volume ratio of the reaction liquid to the ice water is 1:10, ethyl acetate is extracted, the organic layer is washed with saturated brine, dried with anhydrous Na2SO4, and spin-dried to obtain a crude product. The synthesis method has the advantages of mild reaction condition, few side reactions and simple and convenient operation. And the benzyl benzoyl or fluorinated alkane substituted phenol compound obtained by the application has the effect of resisting colon cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to a benzyl benzoyl or fluorinated alkane substituted phenol compound and its synthesis method and application, belonging to the technical field of drug synthesis. BACKGROUND

[0002] Benzyl benzoyl or fluorinated alkane substituted phenol compounds play an important role in organic chemistry, and they have a wide range of applications in drug synthesis, material science, and fine chemicals. These compounds, due to their specific structure and properties, exhibit unique activity and selectivity in chemical reactions, making them important objects of chemical research.

[0003] However, the existing synthesis method of benzyl benzoyl or fluorinated alkane substituted phenol compounds has the problems of multiple side reactions, complex reaction steps, and the need for multiple steps to prepare them. And in the prior art, there is no application of benzyl benzoyl or fluorinated alkane substituted phenol compounds in the treatment of colon cancer. SUMMARY

[0004] To solve the above problems, the purpose of the present application is to provide a benzyl benzoyl or fluorinated alkane substituted phenol compound.

[0005] At the same time, the present application provides a synthesis method of benzyl benzoyl or fluorinated alkane substituted phenol compound, which has mild conditions, less side reactions and simple operation.

[0006] At the same time, the present application provides a benzyl benzoyl or fluorinated alkane substituted phenol compound for preparing an anti-colon cancer drug.

[0007] To solve the above technical problems, the technical solution adopted by the present application is:

[0008] A benzyl benzoyl or fluorinated alkane substituted phenol compound, the molecular formula of which is:

[0009]

[0010] Among them, R 1 including benzyl benzoyl or fluorinated alkane group;

[0011] R 2 including phenyl,

[0012] any one of them.

[0013] Preferably, the benzyl benzoyl group includes

[0014]

[0015] any one of Bn groups.

[0016] Preferably, the fluoroalkyl group comprises

[0017] Preferably, the benzoyl or fluoroalkyl group-substituted phenol compound comprises the following compounds 1-30:

[0018]

[0019] A method for synthesizing a benzoyl or fluoroalkyl group-substituted phenol compound comprises the following steps:

[0020] Step one, 0.3 mmol of o-aminobenzamide, 0.3 mmol of ketone, 10 mol% of I2 and 5 mL of anhydrous ethanol are added at one time into a 10 mL round-bottom flask, stirred at 80°C for 24 h, after the reaction is complete, put it at room temperature, pour the reaction liquid into ice water, the volume ratio of ice water to reaction liquid is 10:1, extract with ethyl acetate, wash the organic layer with saturated brine, dry with anhydrous Na2SO4, spin dry to obtain a crude product;

[0021] Step two, 0.3 mmol, 1.5 equiv of crude product, 0.2 mmol, 1.0 equiv of p-QMs, 2 mol% of 4CzIPN and 2 mL of anhydrous DMF are added into a 10 mL sealed tube by one-pot method, under nitrogen protection, 40W blue light LED, λ=456 nm irradiation, room temperature stirring for 24 h; Step three, after the reaction is complete, the reaction liquid is introduced into ice water, extracted with ethyl acetate, the organic layers are combined, washed with saturated brine, dried with anhydrous Na2SO4, spin dry, then separated by silica gel column with different volume ratios of petroleum ether and ethyl acetate to obtain a benzoyl or fluoroalkyl group-substituted phenol compound.

[0022] Preferably, in step one, the ketone comprises any one of benzil, 4,4'-dimethylbenzil, 4,4'-diisopropylbenzil, 4,4'-di-tert-butylbenzil, 4,4'-dimethoxybenzil, 4,4'-dichlorobenzil, 3,3'-dimethoxybenzil, 3,3'-dichlorobenzil, 2,2'-dimethylbenzil, 1,2-bis(3,4-dimethoxyphenyl)ethane-1,2-dione, 2,2,2-trifluoroacetophenone, 2,2,2-trifluoroacetophenone, diphenyl ketone.

[0023] Preferably, in step three, the mobile phase comprises petroleum ether: ethyl acetate = 5:1, petroleum ether: ethyl acetate = 10:1 or petroleum ether: ethyl acetate = 50:1-10:1.

[0024] The application of a benzyl benzoyl or fluoroalkane substituted phenol compound in the preparation of a drug for resisting colon cancer.

[0025] Compared with the prior art, the application has the following advantages:

[0026] The synthetic method of the application has mild reaction conditions, less side reactions, and simple and convenient operation. The benzyl benzoyl or fluoroalkane substituted phenol compound obtained by the application has the effect of resisting colon cancer.

[0027] The application of 40W blue light (λ=456nm) to the synthesis of the benzyl benzoyl or fluoroalkane substituted phenol compound makes the synthetic route have the characteristics of high efficiency, mild reaction conditions, less side reactions, and simple and convenient operation. DETAILED DESCRIPTION

[0028] The application will be further described in detail below in combination with specific examples. The following examples are only used to illustrate the application and are not used to limit the scope of the application.

[0029] Example 1

[0030] The content of a benzyl benzoyl or fluoroalkane substituted phenol compound, compound 1, is as follows:

[0031] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,2-diphenylethan-1-one (1)

[0032]

[0033] Procedure for synthesis of compound 1: o-aminobenzamide (0.3 mmol, 40.8 mg), benzoyl (0.3 mmol, 63.0 mg), I2(10 mol%, 8 mg), anhydrous ethanol (5 mL) were added into a 10 mL round bottom flask at one time, stirred at 80 °C for 24 h, after the reaction was completed, it was placed at room temperature, the reaction liquid was poured into ice water (V:V = 1:10), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, the crude product (0.3 mmol, 1.5 equiv, 98.4 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg) and anhydrous DMF (2 mL) were added into a 10 mL sealed tube under nitrogen protection, irradiated with 40 W blue light LED (λ = 456 nm), stirred at room temperature for 24 h. After the reaction was completed, the reaction liquid was introduced into ice water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, separated by column with petroleum ether: ethyl acetate = 10:1, to obtain white solid 72.8 mg (91%), M.p. = 91-93 °C.

[0034] 10 mol% of I2 means 0.3 mmol of 10%; I2 molecular weight 253.8 g / mol, 253.8 g / mol x 0.3 mmol x 10% = 7.614 mg, the actual amount of I2 used in the invention is 8 mg.

[0035] 1 H NMR (500 MHz, Chloroform-d) δ 8.04 - 7.98 (m, 2H), 7.51 - 7.46 (m, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.28 (m, 4H), 7.25 - 7.21 (m, 1H), 7.07 (s, 2H), 5.94 (s, 1H), 5.12 (s, 1H), 1.38 (s, 18H). 13 C NMR (126 MHz, Chloroform-d) δ 199.0, 153.0, 139.9, 137.4, 136.0, 132.9, 129.6, 129.2, 129.0, 128.8, 128.7, 127.0, 126.0, 59.4, 34.5, 30.4. HRMS (ESI) m / z: [M+Na] + calcd for C 28 H 32 NaO2 423.2295, found 423.2303.

[0036] Example 2

[0037] The content of compound 2 is as follows: 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2- phenyl-1-(p-tolyl)ethan-1-one (2)

[0038]

[0039] The synthesis process of compound 2 is as follows: o-aminobenzamide (0.3 mmol, 40.8 mg), 4,4'-dimethylbenzil (0.3 mmol, 71.4 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), anhydrous ethanol (5 mL) are added into a 10 mL round-bottom flask at one time, stirred at 80°C for 24 h, after the reaction is complete, put it at room temperature, pour the reaction liquid into ice water (V:V = 1:10), extract with ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous Na2SO4, spin dry, directly add the crude product (0.3 mmol, 1.5 equiv, 106.8 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg) and anhydrous DMF (2 mL) into a 10 mL sealed tube under nitrogen protection, irradiate with a 40W blue light LED (λ = 456 nm), stir at room temperature for 24 h. After the reaction is complete, the reaction liquid is introduced into ice water, extracted with ethyl acetate, the organic layers are combined, washed with saturated brine, dried over anhydrous Na2SO4, spin dry, separated by column with petroleum ether: ethyl acetate = 10:1, to obtain 72.1 mg of white solid (87%), M.p. = 167-169°C. 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 4.4 Hz, 4H), 7.24 - 7.18 (m, 3H), 7.06 (s, 2H), 5.93 (s, 1H), 5.11 (s, 1H), 2.36 (s, 3H), 1.38 (s, 18H). 13 C NMR (126 MHz, Chloroform-d) δ 198.5, 152.9, 143.7, 140.0, 135.9, 134.8, 129.7, 129.4, 129.2, 128.7, 127.0, 126.0, 59.2, 34.5, 30.4, 21.7. HRMS (ESI) m / z: [M+Na] + calcd for C 29 H 34 NaO2 437.2451, found 437.2443.

[0040] Example 3

[0041] The content of compound 3 is as follows:

[0042] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(4-isopropylphenyl)-2-phenylethan-1-one (3)

[0043]

[0044] Synthesis process of compound 3: o-aminobenzamide (0.3 mmol, 40.8 mg), 4,4'-diisopropylbenzil (0.3 mmol, 88.2 mg), I2(10 mol% [10% of 0.3 mmol], 8 mg), anhydrous ethanol (5 mL) were added into a 10 mL round-bottom flask at one time, stirred at 80 °C for 24 h, after the reaction was completed, it was placed at room temperature, the reaction liquid was poured into ice water (V:V = 1:10), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, the crude product (0.3 mmol, 1.5 equiv, 123.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg) and anhydrous DMF (2 mL) were added into a 10 mL sealed tube at one time under nitrogen protection, irradiated with a 40W blue light LED (λ = 456 nm), stirred at room temperature for 24 h. After the reaction was completed, the reaction liquid was introduced into ice water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, separated by column chromatography with petroleum ether: ethyl acetate = 10:1 to obtain 70.8 mg (80%) of white solid, M.p. = 148-150 °C.

[0045] 1 H NMR (500 MHz, Chloroform-d) δ 7.96 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 4.3 Hz, 4H), 7.28 - 7.24 (m, 2H), 7.24 - 7.21 (m, 1H), 7.07 (s, 2H), 5.94 (s, 1H), 5.12 (s, 1H), 2.97 - 2.87 (m, 1H), 1.38 (s, 18H), 1.24 (s, 3H), 1.23 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 198.5, 154.4, 152.9, 140.0, 135.9, 135.2, 129.7, 129.3, 129.2, 128.7, 127.0, 126.8, 126.0, 59.3, 34.5, 34.3, 30.4, 23.8. HRMS (ESI) m / z: [M + Na] + calcd for C 31 H 38 NaO2 465.2764, found 465.2771.

[0046] Example 4

[0047] The content of compound 4 is as follows:

[0048] 1-(4-(tert-butyl)phenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylethan-1-one (4) 3

[0049]

[0050] The synthesis process of compound 4 is as follows: o-aminobenzamide (0.3 mmol, 40.8 mg), 4,4'-di-tert-butyl benzil (0.3 mmol, 96.7 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), anhydrous ethanol (5 mL) were added into a 10 mL round-bottom flask at one time, stirred at 80°C for 24 h, after the reaction was completed, it was placed at room temperature, the reaction liquid was poured into ice water (V:V = 1:10), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, the crude product (0.3 mmol, 1.5 equiv, 132.1 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg) and anhydrous DMF (2 mL) were added into a 10 mL sealed tube at one pot under nitrogen protection, irradiated with a 40W blue light LED (λ = 456 nm), stirred at room temperature for 24 h. After the reaction was completed, the reaction liquid was introduced into ice water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, separated by column with petroleum ether: ethyl acetate = 10:1, to obtain white solid 75.7 mg (83%), M.p. = 136-138°C. 1H NMR (500 MHz, Chloroform-d) δ 8.08 - 7.83 (m, 2H), 7.46 - 7.38 (m, 2H), 7.31 (d, J = 4.5 Hz, 4H), 7.24 - 7.19 (m, 1H), 7.07 (s, 2H), 5.94 (s, 1H), 5.12 (s, 1H), 1.38 (s, 18H), 1.31 (s, 9H). 13 C NMR (126 MHz, Chloroform-d) δ 198.5, 156.6, 153.0, 140.0, 135.9, 134.7, 129.7, 129.2, 129.0, 128.7, 127.0, 126.0, 125.7, 59.3, 35.2, 34.5, 31.2, 30.4. HRMS (ESI) m / z: [M + Na] + calcd for C 32 H 40 NaO2 479.2921, found 479.2924.

[0051] Example 5

[0052] The content of compound 5 is as follows:

[0053] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)-2-phenylethan-1-one (5)

[0054]

[0055] Procedure for synthesis of compound 5: o-Aminobenzamide (0.3 mmol, 40.8 mg), 4,4'-dimethoxybenzil (0.3 mmol, 81.0 mg), I2(10 mol% [10% of 0.3 mmol], 8 mg), anhydrous ethanol (5 mL) were added in one portion to a 10 mL round bottom flask, stirred at 80 °C for 24 h, after the reaction was complete, it was allowed to reach room temperature, the reaction was poured into ice water (V:V = 1 : 10), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous Na2S04, rotary evaporation, the crude was used directly without further purification, crude (0.3 mmol, 1.5 equiv, 116.4 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg) and anhydrous DMF (2 mL) were added in one pot to a 10 mL sealed tube, irradiated under nitrogen atmosphere with a 40 W blue LED (l = 456 nm), stirred at room temperature for 24 h. After the reaction was complete, the reaction was poured into ice water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2S04, rotary evaporation, column separation with petroleum ether: ethyl acetate = 10: 1, white solid 73.1 mg (85%) was obtained, M.p. = 156-158 °C. 1 H NMR (500 MHz, Chloroform-d) d 8.03 - 7.98 (m, 2H), 7.35 - 7.26 (m, 4H), 7.24 - 7.20 (m, 1H), 7.09 - 7.04 (m, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.91 (s, 1H), 5.11 (s, 1H), 3.81 (s, 3H), 1.38 (s, 18H). 13 C NMR (126 MHz, Chloroform-d) d 197.5, 163.4, 152.9, 140.2, 135.9, 131.4, 130.3, 129.9, 129.2, 128.7, 126.9, 126.0, 113.8, 59.0, 55.5, 34.5, 30.4. HRMS (ESI) m / z: [M + H] + calcd for C 29 H 35 O3 431.2581, found 431.2590.

[0056] Example 6

[0057] The content of compound 6 is as follows:

[0058] 1-(4-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylethan-1-one(6) 3

[0059]

[0060] Compound 6 synthesis procedure: o-aminobenzamide (0.3 mmol, 40.8 mg), 4,4'-dichlorobenzoyl (0.3 mmol, 83.4 g), I2(10 mol% [10% of 0.3 mmol], 8 mg), anhydrous ethanol (5 mL) were added into a 10 mL round bottom flask at one time, stirred at 80 °C for 24 h, after the reaction was completed, it was placed at room temperature, the reaction liquid was poured into ice water (V:V = 1:10), extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, the crude product (0.3 mmol, 1.5 equiv, 118.8 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg) and anhydrous DMF (2 mL) were added into a 10 mL sealed tube at one time, irradiated under nitrogen protection with a 40W blue light LED (λ = 456 nm), stirred at room temperature for 24 h. After the reaction was completed, the reaction liquid was introduced into ice water, extracted with ethyl acetate, the organic layers were combined, the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, rotary evaporation, column separation with petroleum ether: ethyl acetate = 10:1 to obtain 66.0 mg (76%) of white solid, M.p. = 152-154 °C. 1 H NMR (500 MHz, Chloroform-d) δ 7.93 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.34-7.29 (m, 2H), 7.28–7.24 (m, 3H), 7.03 (s, 2H), 5.86 (s, 1H), 5.14 (s, 1H), 1.38 (s, 18H). 13 CNMR (126 MHz, Chloroform-d) δ 197.8, 153.1, 139.5, 139.3, 136.1, 135.6, 130.5, 129.2, 129.1, 129.0, 128.8, 127.2, 125.9, 59.5, 34.5, 30.4. HRMS (ESI) m / z: [M+Na] + calcd for C 28 H 31 ClNaO2 457.1905, found 457.1913.

[0061] Example 7

[0062] The contents of compound 7 are as follows:

[0063] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)-2-phenylethan-1-one(7) 4

[0064]

[0065] Synthesis of Compound 7: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.4 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 74.0 mg (86%) of a white solid, Mp = 108-110 °C. 1 H NMR(500MHz,Chloroform-d)δ7.60(d,J=7.7Hz,1H),7.56–7.50(m,1H),7.35–7.28(m,5H),7.27–7.22( m,1H),7.07(s,2H),7.04(dd,J=8.1,2.6Hz,1H),5.92(s,1H),5.13(s,1H),3.79(s,3H),1.38(s,18H). 13C NMR(126MHz,Chloroform-d)δ198.8,159.8,153.0,139.8,138.7,136.0,129.6,129.5,129 .1,128.8,127.1,125.9,121.7,119.5,113.3,59.6,55.5,34.5,30.4.HRMS(ESI)m / z:[M+H] + calcd for C 29 H 35 O3 431.2581, found 431.2573.

[0066] Example 8

[0067] The contents of compound 8 are as follows:

[0068] 1-(3-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylethan-1-one(8)

[0069]

[0070] Synthesis of Compound 8: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dichlorobenzoyl (0.3 mmol, 83.4 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and then treated with saturated brine. The organic layer was washed, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 118.8 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 67.7 mg (78%) of a white solid, Mp = 142-144 °C. 1H NMR(500MHz,Chloroform-d)δ8.04–7.92(m,1H),7.86(d,J=8.1Hz,1H),7.51–7.4 2(m,1H),7.38–7.23(m,6H),7.05(s,2H),5.86(s,1H),5.15(s,1H),1.39(s,18H). 13 C NMR(126MHz,Chloroform-d)δ197.7,153.2,139.3,138.9,136.2,134.9,132.8,130. 0,129.1,129.0,128.9,127.2,127.1,125.9,59.7,34.5,30.4.HRMS(ESI)m / z:[M+Na] + calcd for C 28 H 31 ClNaO2 457.1905, found 457.1900.

[0071] Example 9

[0072] The contents of compound 9 are as follows:

[0073] 1-(3-bromophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylethan-1-one(9)

[0074]

[0075] Synthesis of Compound 9: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dibromobenzoyl (0.3 mmol, 109.8 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After the reaction was allowed to cool to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and then treated with saturated brine. The organic layer was washed, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 145.2 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 73.6 mg (77%) of a white solid at Mp = 158-160 °C. 1 H NMR(500MHz,Chloroform-d)δ8.12(t,J=1.8Hz,1H),7.94–7.87(m,1H),7.67–7.5 9(m,1H),7.34–7.25(m,6H),7.05(s,2H),5.86(s,1H),5.15(s,1H),1.39(s,18H). 13 C NMR(126MHz,Chloroform-d)δ197.6,153.2,139.3,139.1,136.2,135.8,132.1,130.3,1 29.1,129.0,128.9,127.6,127.2,126.0,123.0,59.6,34.5,30.4.HRMS(ESI)m / z:[M+H] + calcd for C 30 H 37 O4 479.1686, found 479.1694

[0076] Example 10

[0077] The contents of compound 10 are as follows:

[0078] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenyl-1-(o-tolyl)ethan-1-one(10)

[0079]

[0080] Synthesis of Compound 10: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2'-dimethylbenzoyl (0.3 mmol, 71.4 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 106.8 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 73.6 mg (89%) of a white solid at Mp = 168-170 °C. 1 H NMR(500MHz,Chloroform-d)δ7.68–7.62(m,1H),7.33(d,J=4.4Hz,4H),7.31–7.27(m,1H), 7.27–7.24(m,1H),7.21–7.17(m,2H),5.78(s,1H),5.12(s,1H),2.39(s,3H),1.38(s,18H). 13 C NMR(126MHz,Chloroform-d)δ203.0,153.0,139.5,139.2,138.3,136.0,131.8,131.0,129. 3,129.2,128.7,128.3,127.1,126.0,125.6,62.1,34.5,30.4,21.1.HRMS(ESI)m / z:[M+Na] + calcd for C 29 H 34 NaO2 437.2451, found 437.2443.

[0081] Example 11

[0082] The contents of compound 11 are as follows:

[0083] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3,4-dimethoxyphenyl)-2-phenylethan-1-one(11)

[0084]

[0085] Synthesis of Compound 11: o-Aminobenzamide (0.3 mmol, 40.8 mg), 1,2-bis(3,4-dimethoxyphenyl)ethane-1,2-dione (0.3 mmol, 99.0 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature and poured into ice water (V:V = 1:10). Ethyl acetate was added... Ester extraction was performed, the organic layer was washed with saturated brine, dried over anhydrous Na₂SO₄, and then evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 134.4 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and then evaporated to dryness. The mixture was separated by column chromatography using petroleum ether:ethyl acetate (10:1) to give 84.7 mg (92%) of a white solid, Mp = 174-176 °C. 1 H NMR(500MHz,Chloroform-d)δ7.73–7.64(m,1H),7.60–7.55(m,1H),7.36–7.28(m,4H),7.24–7.21(m,1H), 7.12–7.06(m,2H),6.83(dd,J=8.4,2.2Hz,1H),5.92(s,1H),5.13(s,1H),3.93–3.83(m,6H),1.39(s,18H). 13 C NMR(126MHz,Chloroform-d)δ197.5,153.1,152.9,148.9,140.2,135.9,130.3,129.8,129.1, 128.7,126.9,125.9,123.6,111.3,110.1,59.1,56.1,55.9,34.4,30.4.HRMS(ESI)m / z:[M+Na] +calcd for C 30 H 36 NaO4 483.2506, found 483.2513.

[0086] Example 12

[0087] The contents of compound 12 are as follows:

[0088] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)-2-(p-tolyl)ethan-1-one(12)

[0089]

[0090] Synthesis of Compound 12: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 61.7 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 72.9 mg (82%) of a white solid, Mp = 181-183 °C. 1 H NMR(500MHz,Chloroform-d)δ7.59(dt,J=7.7,1.3Hz,1H),7.52(dd,J=2.7,1.6Hz,1H),7.29(t,J=8.0Hz,1H),7.22–7.16(m ,2H),7.14–7.09(m,2H),7.08(s,2H),7.06–7.00(m,1H),5.87(s,1H),5.11(s,1H),3.79(s,3H),2.30(s,3H),1.38(s,18H). 13C NMR(126MHz,Chloroform-d)δ198.9,159.8,153.0,138.8,136.8,136.6,135.9,129.7,129.6, 129.5,129.0,125.9,121.6,119.5,113.3,59.3,55.5,34.5,30.4,21.2.HRMS(ESI)m / z:[M+H] + calcd for C 30 H 37 O3 445.2737, found445.2730.

[0091] Example 13

[0092] The contents of compound 13 are as follows:

[0093] 2-(4-(tert-butyl)phenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)ethan-1-one(13)

[0094]

[0095] Synthesis of Compound 13: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 70.1 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (5:1) to obtain 78.8 mg (81%) of a white solid, Mp = 184-186 °C. 1H NMR(400MHz,Chloroform-d)δ7.61(d,J=7.9Hz,1H),7.56–7.49(m,1H),7.40–7.29(m,3H),7.26–7.21(m,2H),7. 13–7.08(m,2H),7.04(dd,J=8.2,2.6Hz,1H),5.88(s,1H),5.12(s,1H),3.79(s,3H),1.39(s,18H),1.28(s,9H). 13 C NMR(101MHz,Chloroform-d)δ198.9,159.8,153.0,149.8,138.8,136.8,136.0,129.6,128 .7,125.9,125.7,121.7,119.5,113.3,59.2,55.5,34.5,31.5,30.4.HRMS(ESI)m / z:[M+H] + calcd forC 33 H 43 O3 487.3207, found 487.3216.

[0096] Example 14

[0097] The contents of compound 14 are as follows:

[0098] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)-2-(4-methoxyphenyl)ethan-1-one(14)

[0099]

[0100] Synthesis of Compound 14: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 64.9 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (5:1) to obtain 70.0 mg (76%) of a white solid, Mp = 180-182 °C. 1 H NMR(500MHz,Chloroform-d)δ7.62–7.57(m,1H),7.55–7.50(m,1H),7.30(t,J=8.0Hz,1H),7.25–7.19(m,2H ),7.08–7.03(m,3H),6.93–6.81(m,2H),5.86(s,1H),5.12(s,1H),3.80(s,3H),3.77(s,3H),1.38(s,18H). 13 C NMR(126MHz,Chloroform-d)δ199.0,159.8,158.6,152.9,138.7,135.9,131.9,130.2,129.9, 129.6,125.8,121.6,119.5,114.2,113.3,58.8,55.5,55.4,34.5,30.4.HRMS(ESI)m / z:[M+Na] + calcd forC 30 H 36 NaO4 483.2506, found 483.2511.

[0101] Example 15

[0102] The contents of compound 15 are as follows:

[0103] 2-([1,1'-biphenyl]-4-yl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)ethan-1-one(15)

[0104]

[0105] Synthesis of Compound 15: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 74.1 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (5:1) to obtain 89.1 mg (88%) of a white solid, Mp = 186-188 °C. 1 H NMR(500MHz,Chloroform-d)δ7.66–7.61(m,1H),7.58–7.53(m,5H),7.44–7.37(m,4H),7.34–7. 29(m,2H),7.13(s,2H),7.07–7.04(m,1H),5.96(s,1H),5.14(s,1H),3.80(s,3H),1.40(s,18H). 13 C NMR(126MHz,Chloroform-d)δ198.7,159.8,153.1,140.9,139.9,139.0,138.7,136.1,129.7,129.5,129. 4,128.9,127.5,127.3,127.2,125.9,121.7,119.6,113.3,59.3,55.5,34.5,30.4.HRMS(ESI)m / z:[M+Na] + calcd forC35 H 38 NaO3 529.2713, found 529.2706.

[0106] Example 16

[0107] The contents of compound 16 are as follows:

[0108] 2-(4-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)ethan-1-one(16)

[0109]

[0110] Synthesis of Compound 16: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 65.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 67.8 mg (73%) of a white solid, Mp = 182-184 °C. 1 H NMR(500MHz,Chloroform-d)δ7.57(d,J=7.8Hz,1H),7.51(s,1H),7.34–7.26(m,3H),7.2 4–7.20(m,2H),7.08–7.02(m,3H),5.88(s,1H),5.16(s,1H),3.79(s,3H),1.38(s,18H). 13C NMR(126MHz,Chloroform-d)δ198.4,159.9,153.2,138.5,138.5,136.2,132.9,130.5,129. 7,129.1,128.8,125.8,121.6,119.7,113.3,58.8,55.5,34.5,30.4.HRMS(ESI)m / z:[M+Na] + calcd for C 29 H 33 ClNaO3 487.2010, found 487.2019.

[0111] Example 17

[0112] The contents of compound 17 are as follows:

[0113] 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)-2-(3-phenoxyphenyl)ethan-1-one(17)

[0114]

[0115] Synthesis of Compound 17: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 77.3 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 75.2 mg (72%) of a white solid at Mp = 188-190 °C. 1H NMR(500MHz,Chloroform-d)δ7.58(d,J=7.8Hz,1H),7.54–7.48(m,1H),7.32–7.24(m,4H),7.08–7.02(m, 5H),7.00–6.94(m,3H),6.87(dd,J=8.2,2.1Hz,1H),5.88(s,1H),5.13(s,1H),3.79(s,3H),1.38(s,18H). 13 C NMR(126MHz,Chloroform-d)δ198.3,159.8,157.4,157.2,153.1,141.8,138.5,136.0,129.9,129.8,129.6,129. 1,125.8,124.1,123.3,121.6,119.8,119.6,118.8,117.5,113.2,59.3,55.4,34.4,30.4.HRMS(ESI)m / z:[M+Na] + calcd for C 35 H 38 NaO4 545.2662, found 545.2670.

[0116] Example 18

[0117] The contents of compound 18 are as follows:

[0118] 2-(3-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)ethan-1-one(18)

[0119]

[0120] Synthesis of Compound 18: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 65.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was then separated by column chromatography using petroleum ether:ethyl acetate (10:1) to obtain 74.3 mg (80%) of a white solid, Mp = 171-173 °C. 1 H NMR(500MHz,Chloroform-d)δ7.60–7.55(m,1H),7.53–7.49(m,1H),7.33(t,J=7.9Hz,1H),7.30–7.28(m,1H), 7.25–7.20(m,2H),7.19–7.16(m,1H),7.10–7.05(m,3H),5.87(s,1H),5.17(s,1H),3.81(s,3H),1.39(s,18H). 13 C NMR(126MHz,Chloroform-d)δ198.1,159.9,153.3,141.9,138.4,136.3,134.5,129.9,129.7,129 .4,128.8,127.3,127.3,125.8,121.6,119.8,113.3,59.1,55.5,34.5,30.4.HRMS(ESI)m / z:[M+H] + calcdfor C 29 H 34 ClO3 465.2191, found 465.2184.

[0121] Example 19

[0122] The contents of compound 19 are as follows:

[0123] 2-(3-bromophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3-methoxyphenyl)ethan-1-one(19)

[0124]

[0125] Synthesis of Compound 19: o-Aminobenzamide (0.3 mmol, 40.8 mg), 3,3'-dimethoxybenzoyl (0.3 mmol, 81.1 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 116.5 mg), p-QMs (0.2 mmol, 1.0 equiv, 74.7 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 100 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in a petroleum ether:ethyl acetate (10:1) column (approximately 300 mL), yielding 76.2 mg (75%) of a white solid at Mp = 178-180 °C. 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J=7.7Hz,1H),7.53–7.48(m,1H),7.43(d,J=8.4Hz,2H),7.31(t,J=8 .0Hz,1H),7.16(d,J=8.3Hz,2H),7.08–6.99(m,3H),5.87(s,1H),5.16(s,1H),3.79(s,3H),1.38(s,18H). 13 C NMR(101MHz,Chloroform-d)δ198.3,159.8,153.2,139.0,138.4,136.2,131.8,130.9,129. 7,129.0,125.7,121.6,121.1,119.7,113.3,58.9,55.5,34.5,30.4.HRMS(ESI)m / z:[M+Na] +calcd for C 29 H 33 BrNaO3 531.1505,found531.1513.

[0126] Example 20

[0127] The contents of compound 20 are as follows:

[0128] 2,6-di-tert-butyl-4-(1,2-diphenylethyl)phenol(20)

[0129]

[0130] Synthesis of Compound 20: o-aminobenzamide (0.3 mmol, 40.8 mg), diphenyl ethyl ketone (0.3 mmol, 58.9 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous Na₂SO₄ and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 94.3 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.9 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 150 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in a petroleum ether:ethyl acetate (10:1) column (approximately 200 mL) to obtain 59.5 mg (77%) of a colorless oil. 1 H NMR(400MHz,Chloroform-d)δ7.28–7.20(m,4H),7.19–7.05(m,4H),7.03–6.9 0(m,4H),5.01(s,1H),4.11(t,J=7.8Hz,1H),3.37–3.21(m,2H),1.36(s,18H). 13C NMR(101MHz,Chloroform-d)δ152.1,144.9,140.9,135.5,135.2,129.3,128.3,1 28.3,128.1,126.1,125.8,124.6,53.4,43.1,34.5,30.4.HRMS(ESI)m / z:[M+Na] + calcd for C 28 H 34 NaO 409.2502, found 409.2511.

[0131] Example 21

[0132] Compound 21 contains the following information:

[0133] 2,6-di-tert-butyl-4-(2,2-difluoro-1-phenylethyl)phenol(21)

[0134]

[0135] Synthesis of Compound 21: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2-difluoroacetophenone (0.3 mmol, 46.8 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate and saturated brine. The organic layer was washed, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 82.3 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.9 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 150 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in a petroleum ether:ethyl acetate (10:1) column (approximately 200 mL) to obtain a yellow oil (53.3 mg, 77%). 1H NMR(500MHz,Chloroform-d)δ7.38–7.30(m,4H),7.29–7.25(m,1H),7.09(s,2H),6. 25(td,J=56.1,4.4Hz,1H),5.16(s,1H),4.30(td,J=16.2,4.4Hz,1H),1.41(s,18H). 13 C NMR(126MHz,Chloroform-d)δ153.2,137.8,136.0,129.2,128.7,127.8,127.4,125.8,117.4(t,J C-F =244.5Hz), 55.2(t,J C-F =20.4Hz), 34.5, 30.4. 19 F NMR(471MHz,Chloroform-d)δ-117.2(d,J=276.9Hz),-118.2(d,J=277.5Hz).HRMS(ESI)m / z:[M+H] + calcd for C 22 H 29 F2O347.2181, found 347.2188.

[0136] Example 22

[0137] Compound 22 is as follows: 4-(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoroethyl)benzonitrile(22)

[0138]

[0139] Synthesis of Compound 22: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2-difluoroacetophenone (0.3 mmol, 46.8 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate and saturated brine. The organic layer was washed, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 82.3 mg), p-QMs (0.2 mmol, 1.0 equiv, 63.9 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 150 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in approximately 200 mL of petroleum ether:ethyl acetate (10:1), yielding 52.0 mg (70%) of a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J=8.4Hz,2H),7.44(d,J=8.1Hz,2H),7.04(s ,2H),6.26(td,J=55.7,3.9Hz,1H),5.24(s,1H),4.50–4.27(m,1H),1.41(s,18H). 13 C NMR(101MHz,Chloroform-d)δ153.6,143.0,136.5,132.4,130.2,126.4(q,J C-F =2.7Hz),125.6,118.8,116.7(t,J C-F =246.1Hz), 111.4, 55.0(t,J) C-F =20.7Hz), 34.5, 30.3. 19 F NMR(376MHz,Chloroform-d)δ-116.1(d,J=279.3Hz),-119.6(d,J=279.0Hz).HRMS(ESI)m / z:[M+H] + calcd forC 23 H 28 F2NO 372.2133, found 372.2128.

[0140] Example 23

[0141] Compound 23 contains the following: 2,6-di-tert-butyl-4-(1-(4-(tert-butyl)phenyl)-2,2-difluoroethyl)phenol (23)

[0142]

[0143] Synthesis of Compound 23: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2-difluoroacetophenone (0.3 mmol, 46.8 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate and saturated brine. The organic layer was washed, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 82.3 mg), p-QMs (0.2 mmol, 1.0 equiv, 70.1 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 150 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in a petroleum ether:ethyl acetate (10:1) column (approximately 230 mL), yielding a yellow oily substance of 67.6 mg (84%). 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J=8.3Hz,2H),7.30–7.24(m,2H),7.11(s,2H),6.23(t d,J=56.2,4.4Hz,1H),5.15(s,1H),4.26(td,J=16.3,4.4Hz,1H),1.41(s,18H),1.30(s,9H). 13 C NMR(101MHz,Chloroform-d)δ153.2,150.2,136.0,134.6(t,J C-F =3.3Hz), 128.8, 127.9(t,J) C-F =3.7Hz),125.8,125.6,117.6(t,J C-F =245.3Hz), 54.9(t,J C-F=20.4Hz), 34.5, 31.5, 30.4. 19 F NMR(376MHz,Chloroform-d)δ-116.9(d,J=275.6Hz),-118.3(d,J=275.6Hz).HRMS(ESI)m / z:[M+H] + calcd for C 26 H 37 F2O 403.2807, found 403.2813.

[0144] Example 24

[0145] Compound 24 contains the following: 4-(1-(3-bromophenyl)-2,2-difluoroethyl)-2,6-di-tert-butylphenol(24)

[0146]

[0147] Synthesis of Compound 24: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2-difluoroacetophenone (0.3 mmol, 46.8 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate and saturated brine. The organic layer was washed, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude product (0.3 mmol, 1.5 equiv, 82.3 mg), p-QMs (0.2 mmol, 1.0 equiv, 74.7 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 150 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in a petroleum ether:ethyl acetate (10:1) column (approximately 270 mL), yielding 70.4 mg (83%) of a yellow oil. 1H NMR(400MHz,Chloroform-d)δ7.48(d,J=8.2Hz,2H),7.21(d,J=8.4Hz,2H),7.07(s,2H),6. 23(td,J=56.0,4.1Hz,1H),5.22(s,1H),4.28(ddd,J=18.4,14.5,4.1Hz,1H),1.43(s,18H). 13 C NMR(101MHz,Chloroform-d)δ153.4,136.7(t,J C-F =3.1Hz),136.2,131.8,131.0,127.2(t,J C-F =3.6Hz),125.6,121.5,117.0(t,J C-F =245.7Hz), 54.6(t,J C-F =20.7Hz), 34.5, 30.4. 19 F NMR(376MHz,Chloroform-d)δ-116.7(d,J=277.9Hz),-119.1(d,J=277.9Hz).HRMS(ESI)m / z:[M+H] + calcd for C 22 H 28 BrF2O 425.1286, found 425.1291.

[0148] Example 25

[0149] Compound 25 is as follows: 2,6-di-tert-butyl-4-(2,2,2-trifluoro-1-phenylethyl)phenol (25)

[0150]

[0151] Synthesis of Compound 25: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2,2-trifluoroacetophenone (0.3 mmol, 52.2 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. Without further treatment, the crude product (0.3 mmol, 1.5 equiv, 87.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 58.9 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was first filtered through approximately 200 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography (approximately 230 mL) using a petroleum ether:ethyl acetate (10:1) column to obtain 64.8 mg (89%) of a yellow oil. 1 H NMR(500MHz,Chloroform-d)δ7.45–7.38(m,2H),7.36(t,J=7.5Hz,2H),7.33– 7.29(m,1H),7.17(s,2H),5.21(s,1H),4.58(q,J=10.2Hz,1H),1.42(s,18H). 13 C NMR(126MHz,Chloroform-d)δ153.6,136.2,136.0,129.2,128.7,127.8,126.1,125.9,125.5,55.6(q,J C-F =27.6Hz),34.5,30.4.HRMS(ESI)m / z:[M+H] + calcd for C 22 H 28 F3O 365.2087, found 365.2080.

[0152] Example 26

[0153] Compound 26 contains the following: 2,6-di-tert-butyl-4-(1-(4-(tert-butyl)phenyl)-2,2,2-trifluoroethyl)phenol (26)

[0154]

[0155] Synthesis of Compound 26: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2,2-trifluoroacetophenone (0.3 mmol, 52.2 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. Without further treatment, the crude product (0.3 mmol, 1.5 equiv, 87.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 70.1 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was first filtered through approximately 200 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography in a petroleum ether:ethyl acetate (10:1) column (approximately 240 mL), yielding 70.1 mg (83%) of a colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.44–7.32(m,4H),7.20(s,2H),5.21(s,1H),4.55(q,J=10.3Hz,1H),1.44(s,18H),1.33(s,9H). 13 C NMR(101MHz,Chloroform-d)δ153.5,150.7,136.0,133.1,128.8,126.7(q,J C-F =281.7Hz),126.3,125.9,125.7,55.3(q,J C-F =27.4Hz),34.6,34.5,31.4,30.4. 19 FNMR(376MHz,Chloroform-d)δ-66.0.HRMS(ESI)m / z:[M+H] + calcd for C 26 H 36 F3O 421.2713, found 421.2706.

[0156] Example 27

[0157] Compound 27 contains the following: 2,6-di-tert-butyl-4-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)phenol (27)

[0158]

[0159] Synthesis of Compound 27: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2,2-trifluoroacetophenone (0.3 mmol, 52.2 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. Without further treatment, the crude product (0.3 mmol, 1.5 equiv, 87.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 65.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The mixture was first filtered through approximately 200 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography (approximately 200 mL) using a petroleum ether:ethyl acetate (10:1) column to obtain 58.1 mg (73%) of a colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.33 (s, 4H), 7.12 (s, 2H), 5.24 (s, 1H), 4.56 (q, J = 10.0Hz, 1H), 1.42 (s, 18H). 13 C NMR(101MHz,Chloroform-d)δ153.7,136.2,134.7,133.8,130.5,128.9,126.4(q,J C-F =60.3Hz), 125.8, 55.0(q,J) C-F =27.5Hz), 34.5, 30.3. 19 F NMR(376MHz,Chloroform-d)δ-66.1.HRMS(ESI)m / z:[M+H] + calcd for C 22 H 27ClF3O 399.1697, found 399.1702.

[0160] Example 28

[0161] Compound 28 contains the following: 2,6-di-tert-butyl-4-(1-(3-chlorophenyl)-2,2,2-trifluoroethyl)phenol (28)

[0162]

[0163] Synthesis of Compound 28: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2,2-trifluoroacetophenone (0.3 mmol, 52.2 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and evaporated to dryness. Without further treatment, the crude product (0.3 mmol, 1.5 equiv, 87.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 65.8 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and evaporated to dryness. The solution was first filtered through approximately 200 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography (approximately 210 mL) using a petroleum ether:ethyl acetate (10:1) column to obtain 60.5 mg of a colorless oil (76%). 1 H NMR (400MHz, Chloroform-d) δ7.39 (s, 1H), 7.36–7.27 (m, 3H), 7.14 (s, 2H), 5.25 (s, 1H), 4.55 (q, J = 9.9Hz, 1H), 1.43 (s, 18H). 13 C NMR(101MHz,Chloroform-d)δ153.8,138.1,136.2,134.6,130.0,129.5,128.1,127.2,126.3(q,J C-F =281.8Hz),125.9,125.3,55.3(q,J C-F =27.7Hz), 34.5, 30.3. 19F NMR(376MHz,Chloroform-d)δ-66.0.HRMS(ESI)m / z:

[0164] [M+H] + calcd for C 22 H 27 ClF3O 399.1697, found 399.1692.

[0165] Example 29

[0166] Compound 29 is as follows: 4-(1-(3-bromophenyl)-2,2,2-trifluoroethyl)-2,6-di-tert-butylphenol (29)

[0167]

[0168] Synthesis of Compound 29: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2,2-trifluoroacetophenone (0.3 mmol, 52.2 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h until the reaction was complete. After cooling to room temperature, the reaction solution was poured into ice water (V:V = 1:10), extracted with ethyl acetate, and saturated salts were collected. The organic layer was washed with water, dried over anhydrous Na₂SO₄, and then evaporated to dryness. Without further treatment, the crude product (0.3 mmol, 1.5 equiv, 87.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 74.7 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and then evaporated to dryness. The solution was first filtered through approximately 200 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography (approximately 220 mL) using a petroleum ether:ethyl acetate (10:1) column to obtain 59.9 mg (68%) of a colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.48(d,J=8.5Hz,2H),7.27–7.24(m,2H),7.10(s,2H),5.23(s,1H),4.53(q,J=10.0Hz,1H),1.41(s,18H). 13C NMR(101MHz,Chloroform-d)δ153.7,136.2,135.2,131.9,130.9,126.3(q,J C-F =281.7Hz),125.8,122.0,55.1(q,J C-F =27.7Hz), 34.5, 30.3. 19 F NMR(376MHz,Chloroform-d)δ-66.1.HRMS(ESI)m / z:[M+H] + calcd for C 22 H 27 BrF3O 443.1192,found 443.1201.

[0169] Example 30

[0170] Compound 30 contains the following: 2,6-di-tert-butyl-4-(2,2,2-trifluoro-1-(o-tolyl)ethyl)phenol(30)

[0171]

[0172] Synthesis of Compound 30: o-Aminobenzamide (0.3 mmol, 40.8 mg), 2,2,2-trifluoroacetophenone (0.3 mmol, 52.2 mg), I2 (10 mol% [10% of 0.3 mmol], 8 mg), and anhydrous ethanol (5 mL) were added all at once to a 10 mL round-bottom flask. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was poured into ice water (V:V = 1:10). Extraction was performed with ethyl acetate, and the solution was saturated. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and then evaporated to dryness. Without further treatment, the crude product (0.3 mmol, 1.5 equiv, 87.7 mg), p-QMs (0.2 mmol, 1.0 equiv, 61.7 mg), 4CzIPN (2 mol%, 15.8 mg), and anhydrous DMF (2 mL) were added directly to a 10 mL sealed tube in a single batch. The mixture was stirred at room temperature for 24 h under nitrogen protection and irradiated with a 40 W blue LED (λ = 456 nm). After the reaction was complete, the reaction solution was transferred to ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, and then evaporated to dryness. The solution was first filtered through approximately 200 mL of petroleum ether:ethyl acetate (50:1), then separated by column chromatography (approximately 220 mL) using a petroleum ether:ethyl acetate (10:1) column to obtain 59.8 mg (79%) of a colorless oil. 1H NMR(500MHz,Chloroform-d)δ7.57(d,J=7.8Hz,1H),7.26 -7.22(m,1H),7.21 -7.14(m,2H),7.11(s,2H),5.18(s,1H),4.79(q,J=10.2Hz,1H),2.30(s,3H),1.39(s,18H). 13 C NMR(126MHz,Chloroform-d)δ153.5,136.7,135.9,134.7,131.0,127.7,126.8(q,J C-F =281.2Hz),126.3,126.3,125.5,51.0(q,J C-F =27.1Hz), 34.5, 30.4, 20.3. 19 F NMR(376MHz,Chloroform-d)δ-65.2.HRMS(ESI)m / z:[M+H] + calcd for C 23 H 30 F3O 379.2243, found 379.2251. Pharmacological activity experiments were conducted on compounds from Examples 1 to 30:

[0173] CCK8 antitumor activity test:

[0174] Logarithmically growing HCT-116, SW-480, and Caco-2 cells were digested with trypsin and counted at a density of 2000 cells / well. These cells were then evenly seeded into 96-well plates and incubated at 37°C and 5% CO2 for 24 hours. The culture medium was removed, and 0.5 μmol / L of drug-containing medium was added. Experimental groups and a control group (5-fluorouracil) were established, with four replicates per group. After drug addition, incubation continued for 24 hours. After incubation, 10 μL of CCK8 solution was added to each well and incubated for 3 hours. The absorbance of each well was measured at 450 nm using a microplate reader. Cell viability of compound 1-30 was calculated based on the absorbance, and the IC50 was calculated. 50 Values. The calculation results are shown in Table 1 below.

[0175] Table 1 IC50 of compounds 50 value

[0176]

[0177]

[0178]

[0179] in conclusion:

[0180] From the CCK8 data, we know that compound 1-30 has a good inhibitory effect on colon cancer cells (HCT-116 cells, SW-480 cells, Caco-2 cells).

[0181] Inhibitory effect on HCT-116 cells, IC50 of compound 1-20 50 The IC50 values ​​of compounds 21-24 were between 79.64 and 172.34 μM. 50 Between 45.08 and 63.57 μM, the IC50 of compound 25-30 50 Between 9.73 and 46.35 μM, compounds 21-30 exhibited significantly better antitumor activity than compounds 1-20.

[0182] Inhibitory effect on SW480 cells, IC50 of compound 1-20 50 The IC50 values ​​of compounds 21-24 were between 51.98 and 149.62 μM. 50 Between 15.46 and 31.00 μM, the IC50 of compound 25-30 50 Between 10.11 and 35.21 μM, compounds 21-30 exhibited significantly better antitumor activity than compounds 1-20, and these compounds showed stronger inhibitory effects on SW480 cells than on HCT-116 cells.

[0183] Inhibitory effect on Caco-2 cells, IC50 of compounds 1-20 50 The IC50 values ​​of compounds 21-24 were between 40.64 and 135.42 μM. 50 Between 9.62 and 19.51 μM, the IC50 of compound 25-30 50 Between 4.90 and 17.72 μM, compound 21-30 exhibited significantly better antitumor activity than compound 1-20. Therefore, compound 21-30 showed stronger inhibitory effects on HCT-116, SW-480, and Caco-2 cells than compound 1-20, indicating that benzylic trifluoromethyl and difluoromethyl substitutions were more effective than benzoyl substitutions.

[0184] Compounds 1-30 generally exhibited stronger inhibitory effects on Caco-2 cells than on HCT-116 and SW-480 cells, with compound 29 (IC50) showing the greatest inhibitory effect. 50 Compound 29 (IC50, 4.90 μM, 9.73 μM) showed stronger inhibitory effects on Caco-2 and HCT-116 cells than the positive control drug 5-fluorouracil. 50 The inhibitory effect of 10.11 μM on SW480 cells was comparable to that of the positive control drug 5-fluorouracil.

[0185] Application of a benzyl benzoyl or fluoroalkane-substituted phenolic compound in the preparation of an anti-colon cancer drug.

[0186] The above description is only a preferred 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. The use of a fluorinated alkane-substituted phenolic compound in the preparation of an anti-colon cancer drug, characterized in that, Molecular formula is: ； Inhibitory effect on HCT-116 cells, IC50 of compound 29 50 The concentration was 9.73 µM, which was superior to the inhibitory effect of the positive control drug 5-fluorouracil; The inhibitory effect on SW480 cells, IC50 of compound 29 was 10.11 µM, comparable to the inhibitory effect of the positive drug 5-fluorouracil; 50 10.11 µM. Inhibitory effect on Caco-2 cells, IC50 of compound 29 50 The concentration was 4.90 µM, which was superior to the inhibitory effect of the positive control drug 5-fluorouracil.

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