Method for synthesizing aryl alkyl ketone compound through reduction cross-coupling reaction and application of aryl alkyl ketone compound

Abstract

The invention discloses an electrochemical synthesis method and anticancer activity of aryl alkyl ketone, and belongs to the field of organic synthesis. A carboxylic acid derivative and a Katritzky salt are respectively used as an acyl electrophilic reagent and an alkyl free radical precursor, in the presence of a catalyst Ni (dme) Br2 and a ligand 2, 2 '-dipyridyl, a single electrolytic tank performs constant-current electrolysis, reductive coupling of the Katritzky salt and the carboxylic acid derivative is realized, the aryl alkyl ketone compounds with diversified structures are synthesized, and the highest yield is 86%. The method is mild in reaction condition, short in reaction time, good in functional group compatibility and wide in substrate application range; meanwhile, the synthesized compound has the activity of obviously inhibiting HCT-116 cancer cell proliferation, so that the compound has the anti-cancer activity on colon cancer and has potential medicinal value.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing aryl alkyl ketone compounds by reduction cross-coupling reaction, and belongs to the field of organic chemistry. BACKGROUND

[0002] Ketone structural units are widely present in many natural products and drug molecules. For example, ketanserin, as a drug with anti-platelet aggregation effect, is often used for anti-hypertension. Irinotecan, by interfering with DNA repair mechanisms, inhibits tumor growth and is a key drug for the treatment of colorectal cancer. Allopregnanolone, as an endogenous neurosteroid of pregnane, is often used for anti-anxiety and anti-depression. Ginkgetin, marine natural products and hesperidin bioactive molecules have significant effects in anti-tumor, antibacterial and anti-inflammatory, respectively. Therefore, it is of great significance to develop green and efficient synthesis methods of ketone compounds.

[0003] The synthesis of ketone compounds by electro / nickel cooperative catalysis is still insufficient. In 2021, the group of Mei Tiansheng reported the reduction cross-coupling reaction of alkyl carboxylic acid and alkyl bromide catalyzed by nickel / electricity, and obtained 1,1-dialkyl ketone products with good yield and regioselectivity. In 2022, the group of Amgoune reported the reduction cross-coupling reaction of alkyl imide and alkyl halide to prepare dialkyl ketone products. In 2022, the group of Xia Wujiong reported the electrochemical reduction coupling reaction of aryl carboxylic acid and alkyl halide to obtain aryl alkyl ketone compounds, but the highest yield was only 42%.

[0004] The above methods mainly use halogenated hydrocarbons as alkyl sources, and the research on aryl alkyl ketones is relatively less, which may be due to the mismatch of the generation rate of aryl nickel species and alkyl radicals. Therefore, it is particularly necessary to develop a method for electrochemically synthesizing aryl ketone compounds with diverse structures. SUMMARY

[0005] In order to overcome the above defects, the present application uses aryl carboxylate compound 1 and Katritzky salt 2 as raw materials to synthesize aryl alkyl ketone compounds under the condition of combination of electrochemistry and nickel catalysis. The method has mild reaction conditions, is environment-friendly and has high yield, and provides a simple, green and efficient way for synthesizing aryl alkyl ketone compounds.

[0006] The method for synthesizing aryl alkyl ketone compounds by reduction cross-coupling reaction according to the present application comprises the following steps: using aryl carboxylate compound 1 and Katritzky salt 2 as raw materials, in the presence of a nickel catalyst, a nitrogen-containing ligand and an organic solvent, a constant current temperature rise reaction in an electrolyte is carried out to obtain aryl alkyl ketone compounds 3-36.

[0007] The method for synthesizing aryl alkyl ketone compounds by reduction cross-coupling reaction according to the present application is represented by a chemical reaction equation as follows:

[0008]

[0009] wherein: R 1 selected from halogen, C1-C4 alkoxy; R 2 selected from C1-C4 alkyl, R is selected from alcohol, aryl ester, C1-C4 alkyl ester, thiophene, pyridine, olefin,

[0010] Further, in the above technical solution, the nitrogen-containing ligand is selected from:

[0011]

[0012] Further, in the above technical solution, the organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, isopropanol, toluene.

[0013] Further, in the above technical solution, the nickel catalyst is selected from Ni(diglyme)Br2, Ni(dme)Cl2, Ni(acac)2, Ni(OTf)2, Ni(OAc)2-4H2O, Ni(BF4)2-6H2O.

[0014] Further, in the above technical solution, the electrolyte is selected from n Bu4NPF6, n Bu4NBF4, n Bu4NClO4, n Bu4NBr, Et4NClO4, Et4NOTs, n Bu4NOAc, n Bu4NOTs.

[0015] Further, in the above technical solution, the constant current refers to the constant current output of the power supply, and the constant current output is 5mA-10mA.

[0016] Further, in the above technical solution, the electrolysis reaction temperature is 25-100℃.

[0017] Further, in the above technical solution, the electrode anode material is selected from zinc sheet, iron sheet, magnesium sheet, aluminum sheet; and the electrode cathode material is selected from foamed nickel, reticular glassy carbon, carbon felt, platinum sheet.

[0018] The application also provides the use of the aryl alkyl ketone obtained by the above method in the preparation of an anticancer drug, and the anticancer is anti-colon cancer (HCT-116).

[0019] The application has the following beneficial effects:

[0020] The application provides a simple, inexpensive and efficient method for synthesizing aryl alkyl ketone compounds, raw materials are easy to obtain, high activity organic metal reagents and stoichiometric reducing agents required in traditional synthesis process are avoided, various aryl alkyl ketone compounds are obtained, the yield is high, and the method has potential application prospects and good anticancer biological activity. DETAILED DESCRIPTION

[0021] The application will be further described by way of examples below, but the application is not limited to the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions or according to the instructions of the products.

[0022] Example 1

[0023]

[0024]

[0025] [a] Unless otherwise specified, the steps of the reaction are as follows: 1a (52.8 mg, 0.2 mmol), 2a (119.8 mg, 1.2 eq), Ni(dme)Br2(6.3 mg, 10 mol%), L5 (4.7 mg, 15 mol%), DMF (4 mL) as the solvent, zinc sheet (1.0 x 1.5 x 0.02 cm 3 ) and foamed nickel (1.0 x 1.5 x 0.02 cm 3 ) are used as the anode and cathode respectively, a constant current of 7 mA is applied in an undivided electrolytic cell at 60°C for 1.7 hours. [b] Separation yield.

[0026] Reaction condition investigation: In the non-divided electrolytic cell, aryl carboxylate 1a (0.2 mmol), Katritzky salt 2a (1.2 eq), Ni(dme)Br2(10 mol%), L5 (15 mol%) and DMF (4 mL) are added. The electrodes are inserted, the power is connected, and a constant current of 7.0 mA is applied at 60°C until the substrate is completely consumed (monitored by TLC or 1 H NMR analysis). After the reaction is terminated, the organic phase is concentrated under vacuum, and column chromatography is performed to obtain compound 3a with a yield of 86%. 1H NMR (600MHz, CDCl3): δ12.99(s,1H),7.97(d,J=8.4Hz,1H),7.85(d,J=9.0Hz,1H),7.76(dd,J=7.8,1.2Hz,1H),7.51-7.48(m,1H ),7.37-7.34(m,1H),7.29-7.26(m,2H),7.23-7.18(m,3H),7.12(d,J=9.0Hz,1H),3.48(t,J=7.2Hz,2H),3.14(t,J=8.4Hz,2H); 13 C NMR (150MHz, CDCl3): δ206.6,163.3,140.9,137.2,131.7,129.6,128.74,128.71,128.6,128.3,126.4,124.6,123.9,119.9,115.4,45.9,31.6.

[0027] Example 2

[0028]

[0029] In a non-separated electrolyzer, aryl carboxylic acid ester (0.2 mmol), Katritzky salt (1.2 eq), Ni(dme)Br2 (10 mol%), L5 (15 mol%), and DMF (4 mL) were added. Electrodes were inserted, power was connected, and the electrolyzer was run at a constant current of 7.0 mA at 60 °C until the substrate was completely consumed (as measured by TLC or...). 1 (H NMR analysis monitoring). After terminating the reaction, the organic phase was concentrated under vacuum, and then compound 7 was obtained by column chromatography in 85% yield. 1 H NMR (400MHz, CDCl3): δ13.01(s,1H),7.99(d,J=8.4Hz,1H),7.87(d,J=8.8Hz,1H),7.78(d,J=8.0Hz,1H),7.54-7.49(m,1H) ,7.38(t,J=7.2Hz,1H),7.16-7.13(m,3H),6.83(d,J=8.4Hz,1H),3.78(s,3H),3.47(t,J=7.6Hz,2H),3.10(t,J=8.0Hz,2H); 13 C NMR (100MHz, CDCl3): δ206.8,163.3,158.2,137.2,132.9,131.7,129.6,1 29.5,128.8,128.2,124.6,123.9,120.0,115.5,114.1,55.4,46.2,30.8.

[0030] Example 3

[0031]

[0032] In a non-divided electrolytic cell, aryl carboxylate (0.2 mmol), Katritzky salt (2.0 eq), Ni(dme)Br2(10 mol%), L5(15 mol%) and DMF (4 mL) were added. The electrode was inserted, power was connected, and the reaction was carried out at 60 °C using a constant current of 7.0 mA until the substrate was completely consumed (by TLC or H NMR analysis monitoring). After the reaction was terminated, the organic phase was concentrated in vacuo, and then compound 10 was obtained by column chromatography in 83% yield. 1 H NMR analysis monitoring). After the reaction was terminated, the organic phase was concentrated in vacuo, and then compound 10 was obtained by column chromatography in 83% yield. 1 H NMR (400 MHz, CDC13): δ 12.93 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.79-6.72 (m, 3H), 3.83 (d, J = 6.4 Hz, 6H), 3.48 (t, J = 8.4 Hz, 2H), 3.11 (t, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, CDC13): δ 206.8, 163.1, 149.0, 147.6, 137.2, 133.5, 131.7, 129.6, 128.7, 128.2, 124.6, 124.0, 120.4, 119.9, 115.6, 111.9, 111.5, 56.0, 55.9, 46.1, 31.3.

[0033] Example 4

[0034] According to the reaction conditions in Examples 2-3, only the reaction substrate was changed, and the following results were obtained:

[0035] Note: a N-Benzoyl succinimides was used.

[0036] Example 5

[0037] In a reaction tube, aryl carboxylate 1b (0.2 mmol), Katritzky salt 2a (2.0 eq), Ni(dme)Br2(10 mol%), L5 (15 mol%) and DMF (4 mL) were added. The electrode was inserted, the power was connected, and the reaction was carried out at 60 °C using a constant current of 7.0 mA until the complete consumption of the substrate (by TLC or 1 H NMR analysis monitoring). After the termination of the reaction, the organic phase was concentrated under vacuum, and then compound 39 was obtained by column chromatography in 80% yield.

[0038]

[0039] 1 H NMR (400 MHz, CDC13): δ 13.08 (s, 1H), 7.74 (dd, J = 11.6, 8.8 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.31-7.26 (m, 2H), 7.23-7.21 (m, 3H), 7.01 (s, 1H), 3.47 (t, J = 8.0 Hz, 2H), 3.15 (t, J = 8.0 Hz, 2H), 2.67 (s, 3H); 13 C NMR (100 MHz, CDC13): δ 206.0, 163.1, 145.0, 141.0, 132.0, 128.7, 128.6, 128.4, 127.9, 126.4, 125.4, 125.2, 123.9, 120.5, 114.5, 45.8, 31.8, 20.3.

[0040] Example 6

[0041]

[0042] In a reaction tube, aryl carboxylate 1b (0.2 mmol), Katritzky salt 2a (2.0 eq), Ni(dme)Br2(10 mol%), L5 (15 mol%) and DMF (4 mL) were added. The electrode was inserted, the power was connected, and the reaction was carried out at 60 °C using a constant current of 7.0 mA until the complete consumption of the substrate (by TLC or 1 H NMR analysis monitoring). After the termination of the reaction, the organic phase was concentrated under vacuum, and then compound 39 was obtained by column chromatography in 80% yield. 1H NMR (400 MHz, CDC13): δ 13.03 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.33-7.30 (m, 2H), 7.24 (s, 2H), 7.16 (d, J = 9.2 Hz, 1H), 3.52 (t, J = 7.6 Hz, 2H), 3.18 (t, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, CDC13): δ 206.0, 163.1, 150.6, 141.0, 132.3, 128.7, 128.6, 127.7, 127.5, 126.4, 125.4, 124.9, 123.9, 118.6, 114.5, 45.8, 31.8, 26.3, 14.2.

[0043] Example 7

[0044] In a reaction tube, aryl carboxylate 1d (0.2 mmol), Katritzky salt 2a (2.0 eq), Ni(dme)Br2(10 mol%), L5 (15 mol%) and DMF (4 mL) were added. The electrode was inserted, the power supply was connected, and the reaction was run at 60 °C using a constant current of 7.0 mA until complete consumption of the substrate (by TLC or H NMR analysis monitoring). After the reaction was terminated, the organic phase was concentrated in vacuo, and then compound 41 was obtained by column chromatography in 72% yield. 1 H NMR analysis monitoring). After the reaction was terminated, the organic phase was concentrated in vacuo, and then compound 41 was obtained by column chromatography in 72% yield.

[0045]

[0046] 1 H NMR (400 MHz, CDC13): δ 13.03 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.33-7.30 (m, 2H), 7.24 (s, 2H), 7.16 (d, J = 9.2 Hz, 1H), 3.52 (t, J = 7.6 Hz, 2H), 3.18 (t, J = 7.6 Hz, 2H); 13CNMR (100 MHz, CDC13): δ 206.6, 163.3, 140.9, 137.3, 131.7, 129.7, 128.8, 128.7, 128.6, 128.3, 126.4, 124.6, 124.0, 120.0, 115.4, 45.9, 31.6.

[0047] Example 8

[0048]

[0049] In a reaction tube, aryl carboxylate 1e (0.2 mmol), Katritzky salt 2a (2.0 eq), Ni(dme)Br2(10 mol%), L5 (15 mol%) and DMF (4 mL) were added. The electrode was inserted, the power source was connected and the reaction was carried out at 60 °C using a constant current of 7.0 mA until complete consumption of the substrate (by TLC or H NMR analysis monitoring). After the termination of the reaction, the organic phase was concentrated in vacuo and then compound 42 was obtained by column chromatography in 74% yield. 1 H NMR analysis monitoring). After the termination of the reaction, the organic phase was concentrated in vacuo and then compound 42 was obtained by column chromatography in 74% yield. 1 H NMR (400 MHz, CDC13): δ 13.00 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.40-7.36 (m, 1H), 7.31-7.27 (m, 2H), 7.24-7.21 (m, 2H), 7.14 (d, J = 9.2 Hz, 1H), 3.51 (t, J = 7.2 Hz, 2H), 3.16 (t, J = 8.0 Hz, 2H); 13 CNMR (100 MHz, CDC13): δ 206.6, 163.3, 140.9, 137.3, 131.7, 129.7, 128.76, 128.73, 128.6, 128.3, 126.4, 124.6, 124.0, 120.0, 115.4, 45.9, 31.7.

[0050] Example 9

[0051] In a reaction tube, aryl carboxylate 1e (0.2 mmol), Katritzky salt 2a (2.0 eq), Ni(dme)Br2(10 mol%), L5 (15 mol%) and DMF (4 mL) were added. The electrode was inserted, the power source was connected and the reaction was carried out at 60 °C using a constant current of 7.0 mA until complete consumption of the substrate (by TLC or H NMR analysis monitoring). After the termination of the reaction, the organic phase was concentrated in vacuo and then compound 42 was obtained by column chromatography in 74% yield. 1H NMR analysis monitoring). After the reaction was terminated, the organic phase was concentrated under vacuum, and then compound 43 was obtained by column chromatography with a yield of 79%.

[0052]

[0053] 1 H NMR (400 MHz, CDC13): δ 12.70 (s, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 3H), 8.01 (dd, J = 9.2, 2.8 Hz, 1H), 7.11-7.09 (m, 2H), 3.88 (s, 3H), 3.44 (t, J = 8.0 Hz, 2H), 3.13 (t, J = 8.0 Hz, 2H); 13 C NMR (100 MHz, CDC13): δ 206.4, 161.5, 156.0, 140.9, 136.1, 129.9, 129.8, 128.7, 128.6, 126.4, 126.3, 126.0, 120.8, 120.3, 119.6, 115.7, 115.4, 108.7, 55.5, 46.0, 31.6.

[0054] Example 10

[0055] The anti-cancer activity of the compounds was evaluated by cell anti-proliferation activity studies using CCK8 analysis. First, cells were seeded into 96-well plates at a density of 5000 cells per well in 100 μL of culture medium and incubated at 37 °C in a 5% CO2 environment overnight. The next day, 100 μL of different concentrations of the test compound diluted with culture medium was added to each well, and then the cells were incubated at 37 °C in a 5% CO2 environment for 72 hours. Then, 10 μL of CCK8 was added to each well, and the 96-well plate was incubated at 37 °C for 2 hours. The absorbance at 450 nm was measured using a multifunctional enzyme label instrument (Perkin Elmer), and the IC 50 values were calculated using GraphPad Prism 6.0 software. All experiments were performed in triplicate. HCT-116 colon cancer cells were selected as the research object, and 5-fluorouracil (5-FU) was used as the positive control of the drug, and the results were as follows.

[0056]

[0057] The activity results show that the aryl alkyl ketone compound provided by the application can inhibit the proliferation activity of HCT-116 cells, wherein compounds 13, 15 and 30 have a significant inhibitory effect on proliferation. The activity results suggest that the compounds have important medicinal value in the treatment of colon cancer.

[0058] The above examples describe the basic principles, main features and advantages of the application. Those skilled in the art should understand that the application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the application. Without departing from the scope of the principles of the application, various changes and improvements can be made to the application, and these changes and improvements all fall within the scope of the application.

Claims

1. A method of synthesizing an arylalkanone compound, characterized by, The method comprises the following steps: taking aryl carboxylic acid ester compound 1 and Katritzky salt 2 as raw materials, and performing constant current temperature rising reaction in an electrolyte in the presence of a nickel catalyst, a nitrogen-containing ligand and an organic solvent to obtain aryl alkyl ketone compound 3-36: Where: R 1 Selected from halogens and C1-C4 alkoxy groups; R 2 Selected from C1-C4 alkyl groups, where R is selected from alcohols, aryl esters, alkyl esters, thiophenes, pyridines, alkenes, etc.

2. The method of synthesizing arylalkanone compounds according to claim 1, wherein, The nitrogen-containing ligand is selected from:

3. The method of synthesizing aryl alkyl ketone compounds according to claim 1, wherein: The organic solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, isopropanol and toluene.

4. The method of synthesizing arylalkanone compounds according to claim 1, wherein: The nickel catalyst is selected from Ni(dme)Cl2, Ni(diglyme)Br2, Ni(acac)2, Ni(OTf)2, Ni(OAc)2-4H2O and Ni(BF4)2-6H2O.

5. The method of synthesizing arylalkanone compounds according to claim 1, wherein: The electrolyte is selected from n Bu4NPF6, n Bu4NBF4, n Bu4NClO4, n Bu4NBr, Et4NClO4, Et4NOTs, n Bu4NOAc, n Bu4NOTs.

6. The method of synthesizing arylalkanone compounds according to claim 1, wherein: The constant current refers to the constant current output of a power supply, and the constant current output is 5mA-10mA.

7. The method for synthesizing aryl ketone compounds according to claim 1, characterized in that: The temperature rising reaction temperature is 25-100 DEG C.

8. The process for synthesis of aryl alkyl ketone compound as claimed in claim 1 wherein: The electrode anode material is selected from zinc sheet, iron sheet, magnesium sheet and aluminum sheet; and the electrode cathode material is selected from foamed nickel, reticular glassy carbon, carbon felt and platinum sheet.

9. Application of aryl alkyl ketone obtained by any one of the methods in claims 1-8 in preparation of an anticancer drug, wherein the anticancer is anticolon cancer.

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