An electrochemical method for the selective oxidation of benzylic carbon-hydrogen bonds

Abstract

The application discloses a method for electrochemical oxidation of selective benzyl carbon-hydrogen bond. The application provides a preparation method of compound I, which comprises the following steps: in the presence of a catalyst and an alkaline reagent, compound II is subjected to electrolytic oxidation reaction to generate compound I in a solvent. The preparation method provided by the application combines a large steric hindrance hydrogen atom transfer reagent N-hydroxymaleimide analogue and organic electro-synthesis for the first time, and obviously improves the regional selectivity of the reaction.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for electrochemical oxidation of selective benzylic C-H bond. BACKGROUND

[0002] Electrochemical oxidation reaction has the advantages of mild conditions, less pollution and convenient operation. Unlike traditional thermal chemical reaction, electrochemical oxidation reaction often needs to generate free radicals through base-promoted PCET process on the surface of the electrode, and then hydrogen atom transfer reaction occurs to generate intermediates such as benzyl radical (10.1038 / nature17431; 10.1248 / cpb.35.1372). After the generation of free radicals, they are captured by oxygen to obtain products.

[0003] Poor regioselectivity is a long-standing challenge in electrochemical oxidation reaction. In the traditional electrochemical oxidation reaction of benzyl, N-hydroxyphthalimide (NHPI) is difficult to distinguish between the benzyl C-H bonds with similar electrical properties but different steric hindances, and its activity is too high, which easily leads to over-oxidation of the substrate, thereby limiting its application in reactions requiring high selectivity.

[0004] The present application first combines large steric hydrogen atom transfer reagent N-hydroxymaleimidyl hydroxylamine (NHMI) analogs with organic electro-synthesis. Under electrochemical conditions, the reaction selectivity is significantly improved by catalyst structure regulation compared with the catalytic effect of NHPI and its analogs. This innovative method effectively solves the problem of poor regioselectivity in electrochemical oxidation field and provides a new solution for high selectivity reaction. SUMMARY

[0005] The technical problem solved by the present application is to overcome the deficiencies of the prior art and provide a method for high-selectivity oxidation of benzylic C-H bond under electrochemical conditions. The present application provides a method for electrochemical oxidation of selective benzylic C-H bond. The method provided by the present application has the effect of realizing high regioselectivity in the field of electrochemical oxidation.

[0006] The present application solves the above technical problems by the following technical solutions.

[0007] The present application provides a preparation method of compound I, which comprises the following steps: in the presence of a catalyst and a basic reagent, compound II is subjected to electrolytic oxidation reaction to generate compound I in a solvent;

[0008] ;

[0009] wherein R is C1-C 10 alkyl or ;

[0010] n is 0, 1, 2 or 3; R1 is C4-C12 cycloalkyl;

[0011] The catalyst is ; wherein T is independently phenyl or tert-butyl; m is 0, 1 or 2;

[0012] The solvent is a halogenated alkane solvent, a ketone solvent or a nitrile solvent.

[0013] In some embodiments of the present application, the solvent can be a halogenated alkane solvent, a ketone solvent or a nitrile solvent, for example 1,2-dichloroethane, acetone or acetonitrile; preferably 1,2-dichloroethane.

[0014] In some embodiments of the present application, the basic reagent is pyridine substituted with one or more C1-C4 alkyl groups; the C1-C4 alkyl group is preferably methyl, and the basic reagent is preferably 2,6-dimethylpyridine.

[0015] In some embodiments of the present application, the electrolytic oxidation reaction is carried out under oxygen conditions, for example in a 1 atm oxygen atmosphere.

[0016] In some embodiments of the present application, the oxidation reaction is carried out in the presence of an electrolyte. The electrolyte can be a Buffer salt or an organic ammonium salt, for example [PyH]BF4, [2,6-lutH]BF4, [2,4,6-ColH] BF4, n Bu4ClO4, n Bu4NCl or n Bu4NBF4, preferably [2,6-lutH]BF4.

[0017] In some embodiments of the present application, the reaction device for the electrolytic oxidation reaction comprises an anode electrode, a cathode electrode and an electrolyte; the anode electrode can be a carbon felt electrode, a carbon plate, a platinum electrode or a reticulated vitreous carbon electrode (RVC) (preferably a carbon felt electrode); the cathode electrode is preferably a platinum sheet electrode, a carbon felt electrode, a carbon plate or a reticulated vitreous carbon electrode (RVC), preferably a platinum sheet electrode.

[0018] In some embodiments of the present application, in the electrolytic oxidation reaction, the molar volume ratio of the electrolyte to the solvent can be 0.05-0.4 mol / L, preferably 0.1 mol / L.

[0019] In some embodiments of the present application, the reaction current of the electrolytic oxidation reaction is 0.5-1.5 mA; preferably 0.5 mA.

[0020] In some embodiments of the present application, the voltage of the electrolytic oxidation reaction is conventional in the art, and can be controlled by the reaction current, generally not more than 2.5 V, for example, 2.0-2.5 V; preferably 2.3 V or 2.5 V.

[0021] In some embodiments of the present application, the reaction temperature of the electrolytic oxidation reaction can be 21-50 °C, for example, 30 °C.

[0022] In some embodiments of the present application, the progress of the electrolytic oxidation reaction is detected by conventional monitoring methods for such reactions in the art, for example, TLC, etc. Preferably, the reaction endpoint is the complete conversion of compound II or the non-formation of compound I. The time of the electrolytic oxidation reaction can be 24-36 h; preferably 30 h.

[0023] In some embodiments of the present application, in the electrolytic oxidation reaction, the anode electrode is at least immersed in the solution by 1 cm.

[0024] In some embodiments of the present application, the concentration of compound II in the solvent can be 0.01-0.05 mmol / mL, preferably 0.025 mmol / mL.

[0025] In some embodiments of the present application, the molar ratio of compound II to the catalyst can be 1:(0.1-0.5), preferably 1:0.2.

[0026] In some embodiments of the present application, the molar ratio of compound II to the electrolyte can be 1:(2-5), preferably 1:4.

[0027] In some embodiments of the present application, the molar ratio of compound II to the basic agent can be 1:(0.5-5), preferably 1:0.5.

[0028] In some embodiments of the present application, the electrolytic oxidation reaction comprises the following reaction step: after mixing and dissolving compound II, the catalyst, the electrolyte and the basic agent in the solvent in the presence of oxygen, electrolytic oxidation reaction is carried out.

[0029] In some embodiments of the present application, the electrolytic oxidation reaction further comprises the following steps: after the reaction, an ester solvent (for example, ethyl acetate) is added, washed (for example, with water), concentrated, and compound I is obtained by silica gel column chromatography purification; the silica gel column chromatography can use conventional operations and mobile phase ratios in the art, for example, eluted with ethyl acetate / petroleum ether = 2:98.

[0030] In some embodiments of the present application, the C1-C 10 alkyl is linear or branched C1-C10 Alkyl; for example, linear or branched C1-C8 alkyl (for example, linear or branched C4-C8 alkyl); preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 、 、 、 、 、 、 or .

[0031] In some embodiments of the present invention, the C4-C 12 Cycloalkyl is C4-C 12 Monocyclic, bicyclic or bridged cycloalkyl groups; for example 、 、 、 or .

[0032] In some embodiments of the present invention, the compound I is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0033] In some embodiments of the present invention, the compound II is: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0034] In some embodiments of the present invention, the catalyst is 、 、 or .

[0035] In some embodiments of the present application, the raw material of the electrolytic oxidation reaction is the compound II, the catalyst, oxygen, 2,6-lutidine tetrafluoroborate, 2,6-lutidine and dichloroethane; wherein the catalyst is .

[0036] The present application also provides a preparation method of the compound III, which comprises the following steps: generating the compound III from the compound IV through electrolytic oxidation reaction in the presence of a catalyst and a basic reagent in a solvent;

[0037]

[0038] wherein R2 is cyclopropyl, phenyl or phenyl substituted with one or more R 2-1 ; R is C1-C4 alkyl unsubstituted or substituted with one or more halogens or C1-C4 alkoxy unsubstituted or substituted with one or more halogens; 2-1

[0039] The solvent, the catalyst, the basic reagent and the electrolytic oxidation reaction are as described above.

[0040] In some embodiments of the present application, the halogen is independently F, Cl, Br or I.

[0041] In some embodiments of the present application, the compound III is any one of the following: , , or .

[0042] In some embodiments of the present application, the compound IV is any one of the following: , , or .

[0043] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining various preferred examples of the present application.

[0044] The reagents and raw materials used in the present application are commercially available.

[0045] The positive progress effect of the present application is that the present application combines N-hydroxymaleimide (NHMI) derivatives and organic electro-synthesis for the first time, thereby improving the regioselectivity of the reaction and reducing the peroxidation phenomenon. DETAILED DESCRIPTION

[0046] ​The application will be further described in the following by way of examples without limiting the application to the described examples. The experimental methods in the following examples, for which no specific conditions are indicated, are carried out in accordance with the usual methods and conditions, or in accordance with the instructions of the commercial suppliers.

[0047] 1. Catalyst synthesis:

[0048] The synthesis of N-hydroxymaleimide can be referred to (T. Kato, K. Maruoka, Angewandte Chemie International Edition 2020, 59, 14261-14264);

[0049]

[0050] The synthesis route of catalyst I is as follows:

[0051] .

[0052] 2. Electrochemical device setup

[0053] Take a 25 ml three-necked flask, punch a hole in the rubber plug to pass through the electrode and ensure airtightness, the anode is a carbon felt electrode (10 x 3 x 25 mm), the cathode is a platinum sheet electrode (10 x 10 mm), then add the substrate (0.2 mmol, 1 equiv.) to the flask, electrolyte (2,6-dimethylpyridine tetrafluoroboric acid, 0.1 M, 0.8 mmol), bulky catalyst (0.04 mmol, 0.2 equiv.). After adding, add a three-way stopcock to the three-necked flask and exchange oxygen, then add 2,6-dimethylpyridine (0.5 equiv., 0.1 mmol, 10.7 mg), solvent 1,2-dichloroethane (8 mL). After adding, the reaction system is placed in a 30°C oil bath and stirred at a speed of 800 rpm for 15 min until all the solid materials are dissolved.

[0054] 3. Electrolysis parameters:

[0055] Connect the anode and cathode to a direct current source and set the reaction current to 0.5 mA and the maximum reaction voltage to 2.5 V. Fine-tune the anode position so that it is at least 1 cm immersed in the solution, and the initial voltage is about 2.3 V, and electrolyze for 30 h.

[0056] 4. Reaction processing:

[0057] To the system, dilute brine and a large amount of ethyl acetate were added for extraction, and the organic phase obtained by extraction was dried, concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 98:2), and the main product was a small steric hindrance oxidation product, which was yellow or orange when colored with phenylhydrazine color developing solution.

[0058] Region selectivity determination:

[0059] A small amount of the extracted reaction solution was diluted to an appropriate concentration and detected using a GC-FID detector to detect the region selectivity, and the specific method was as follows:

[0060] Chromatographic column: Agilent HP-5ms Ultra Inert 0 ℃-325 ℃ (350 ℃): 30 m x 250 μm x 0.25 μm.

[0061] Inlet: 260 ℃, split injection, split ratio: 20 / 1, carrier gas flow: 2 mL / min (He),

[0062] Pressure: 21.844 psi, injection volume: 1 μL (using an automatic injector).

[0063] Column oven: 60 ℃ (hold for 2 min) to 280 ℃ (hold for 2 min) at 15 ℃ / min.

[0064] Detector: 280 ℃, H2: 30 mL / min, air: 400 mL / min, tail gas (N2): 25 mL / min.

[0065] Example 1:

[0066]

[0067] Under an oxygen environment, a three-necked flask was added with compound II (0.2 mmol, 1.0 equivalent), a catalyst (20 mol%, 0.04 mmol, 0.2 equivalent) and 2,6-dimethylpyridine tetrafluoroboric acid (LutHBF4) (0.8 mmol, 4.0 equivalents, 0.1 M). Subsequently, 2,6-dimethylpyridine (0.1 mmol, 0.5 equivalent) and dichloroethane (8 mL) were added to the mixture through a septum at 30 °C. The mixture was stirred for 15 minutes to dissolve the electrolyte before electrolysis. Then, the mixture was subjected to electrolysis (0.5 mA, < 2.5 V) for 30 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water to remove the electrolyte, and then concentrated under vacuum. The residue was further purified by silica gel column chromatography (eluted with ethyl acetate / petroleum ether = 2:98) to obtain the main product as compound I and the by-product as compound III.

[0068] The following compounds were prepared according to the synthesis conditions of Example 1:

[0069] Table 1

[0070] .

[0071] As can be seen from Table 1, the reaction has good reactivity for substrates with different steric groups. Compared with NHPI, the regioselectivity of NHMI catalyst is better, and the selectivity for benzyl hydrocarbons with less steric hindrance is higher.

[0072] The characterization results of the compounds obtained in Table 1 are as follows:

[0073] Compound 1

[0074] 1-(4-(Cyclohexylmethyl)phenyl)ethan-1-one (1a)

[0075]

[0076] Wherein, compound II is 1-(cyclohexylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0077] Yellow oil (27.2 mg, 63%). 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.5Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 2.58 (s, 3H), 2.54 (d, J = 7.2 Hz, 2H), 1.90 – 1.48 (m, 7H), 1.23 – 1.13 (m, 2H), 1.01 – 0.94 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 198.0, 147.4, 134.9, 129.4, 128.3, 44.1, 39.7, 33.1, 26.6, 26.5, 26.2. Total yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 77%; main product:byproduct (selectivity) = 87:13; GC-FID determination (temperature: 180°C 3 min to 280°C 2 min, heating at 10°C / min); t R = 5.640 min (byproduct), t R = 5.939 min (main product).

[0078] Compound 2

[0079] 1 -(4-(cyclopentylmethyl)phenyl)ethan-1 -one

[0080]

[0081] wherein compound II is 1 -(cyclopentylmethyl)-4-ethylbenzene and the catalyst is catalyst I;

[0082] Colorless oil (17.5 mg, 45%). 1 H NMR (400 MHz, CDC13) δ 7.87 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 2.75 (d, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.10 - 1.98 (m, 2H), 1.91 - 1.79 (m, 2H), 1.77 - 1.68 (m, 2H), 1.46 - 1.34 (m, 1H). 13 C NMR (101 MHz, CDC13) δ 198.1, 147.3, 135.1, 128.8, 128.6, 43.1, 37.1, 28.3, 26.7, 18.5. Total yield (g 1 H NMR (400 MHz, CDC13) 14 μL CH2Br2 as internal standard) = 58% main product: by-product (selectivity ratio) = 62:38 The regioselectivity is determined by 1 H NMR (400 MHz, CDC13).

[0083] Compound 3

[0084] 1 -(4-(cyclopentylmethyl)phenyl)ethan-1 -one

[0085]

[0086] wherein compound II is 1 -(cyclopentylmethyl)-4-ethylbenzene and the catalyst is catalyst I;

[0087] Yellow oil (23.9 mg, 58%). 1H NMR (400 MHz, CDC13) δ 7.87 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 2.67 (d, J = 7.6 Hz, 2H), 2.59 (s, 3H), 2.17 - 2.00 (m, 1H), 1.76 - 1.48 (m, 7H), 1.22 - 1.12 (m, 1H). 13 C NMR (101 MHz, CDC13) δ 198.1, 148.4, 135.0, 129.1, 128.5, 42.2, 41.8, 32.6, 26.7, 25.0. Total yield 1 H NMR (400 MHz, CDC13) 14 μL CH2Br2 as internal standard) = 54%; main product: side product (selectivity ratio) = 76:24; GC-FID assay (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min); t R = 12.126 min (side product), t R = 12.305 min (main product).

[0088] Compound 4

[0089] 1-(4-(Cycloheptylmethyl)phenyl)ethan-1-one

[0090]

[0091] wherein compound II is 1-(cycloheptylmethyl)-4-ethylbenzene and the catalyst is catalyst I;

[0092] Yellow oil (23.5 mg, 51%). 1 H NMR (400 MHz, CDC13) δ 7.87 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 2.61 - 2.47 (m, 5H), 1.87 - 1.75 (m, 1H), 1.71 - 1.53 (m, 7H), 1.52 - 1.43 (m, 2H), 1.43 - 1.31 (m, 2H), 1.25 - 1.15 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 198.1, 148.0, 135.1, 129.5, 128.5, 44.6, 41.4, 34.5, 28.5, 26.7, 26.4. IR (neat): 2921, 2853, 1764, 1682, 1605, 1358, 1265, 1055, 800 cm–1. HRMS (EI-QTOF) calcd. for C16H22O: 230.1665; found: 230.1663. Total yield ( 1 H NMR (400 MHz, CDCl3) 14μL CH2Br2 as internal standard) = 68%; main product: side product (selectivity ratio) = 89:11; GC-FID determination (temperature: 196 °C 2 min to 280 °C 2 min, ramping at 10 °C / min); t R = 5.527 min (side product), t R = 5.834 min (main product).

[0093] Compound 5

[0094]

[0095]

[0096] wherein compound II is 1-cyclohexyl-4-ethylbenzene and catalyst is catalyst I;

[0097] Yellow oil (24.3 mg, 60%). 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 2.58 (s, 3H), 1.93 – 1.71 (m, 5H), 1.53 – 1.16 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 198.0, 153.9, 135.2, 128.7, 127.2, 44.8, 34.2, 26.8, 26.7, 26.1. Total yield ( 1H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 61%; main product:byproduct (selectivity) = >99:1; GC-FID determination (temperature: 60°C 2 min to 280°C 2 min, heating at 15°C / min); t R = 12.244 min (main product).

[0098] Compound 6

[0099] 4-n-pentylacetophenone

[0100]

[0101] Wherein, compound II is 1-(n-pentyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0102] Colorless oily liquid (17.6 mg, 49%). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.6Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 2.70 – 2.63 (m, 2H), 2.58 (s, 3H), 1.74 –1.53 (m, 2H), 1.41 – 1.23 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz,CDCl3) δ 198.0, 148.9, 134.9, 128.6, 128.5, 36.0, 31.4, 30.8, 26.6, 22.5,14.0.Total yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 64%; main product:byproduct (selectivity) = 80:20; GC-FID determination (temperature: 60°C 2 min to 280°C 2 min, heating at 15°C / min); t R = 10.904 min (by-product), t R = 11.000 min (main product).

[0103] Compound 7

[0104] 1-(4-(Isopropylmethyl)phenyl)ethan-1-one

[0105]

[0106] wherein compound II is 1 -(isopropylmethyl)-4-ethylbenzene and the catalyst is catalyst I;

[0107] Yellow oil liquid (23.1 mg, 61%). 1 H NMR (400 MHz, CDC13) δ 7.88 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 2.59 (s, 3H), 2.53 (d, J = 7.2 Hz, 2H), 1.96 - 1.83 (m, 1H), 0.91 (d, J = 6.8 Hz, 6H). 13 C NMR (101 MHz, CDC13) δ 198.1, 147.7, 135.1, 129.4, 128.4, 45.5, 30.2, 26.7, 22.5. Total yield 1 H NMR (400 MHz, CDC13) 14 μL CH2Br2 as internal standard) = 86%; main product: side product (selectivity ratio) = 88: 12; GC-FID determination (temperature: 112 °C 3 min to 172 °C 3 min, ramping at 10 °C / min); t R = 7.508 min (side product), t R = 7.765 min (main product).

[0108] Compound 8

[0109] 1 -(2-ethylbutylphenyl) ethan-1 -one

[0110]

[0111] wherein compound II is 1 -(2-ethylbutyl)-4-ethylbenzene and the catalyst is catalyst I;

[0112] Yellow oil liquid (23.1 mg, 61%). 1 H NMR (400 MHz, CDC13) δ 7.88 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 2.59 (s, 3H), 2.53 (d, J = 7.2 Hz, 2H), 1.96 - 1.83 (m, 1H), 0.91 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz,CDCl3) δ 198.1, 148.1, 135.0, 129.5, 128.4, 42.6, 39.9, 26.7, 25.1, 10.9. Total yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 71%; main product:byproduct (selectivity) = 92:8; GC-FID determination (temperature: 60°C 2 min to 280°C 2 min, heating at 15°C / min); t R =10.929 min (by-product), t R = 11.470 min (main product).

[0113] Compound 9

[0114] 1-(4-(tert-Butylmethyl)phenyl)ethan-1-one

[0115]

[0116] Wherein, compound II is 1-(tert-butylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0117] Yellow oily liquid (31.6 mg, 83%). 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 2.67 (s, 3H), 2.63 (s, 2H), 0.99 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 198.2, 145.8, 135.1, 130.7, 127.9, 50.3, 32.1,29.5, 26.7. Total yield ( 1 H NMR (400 MHz, CDCl3) (14 μL CH2Br2 as internal standard) = 97%; main product:byproduct (selectivity) = >99:1; GC-FID determination (temperature: 130°C for 3 min to 190°C for 3 min, heating at 10°C / min); t R = 6.671 min (main product).

[0118] Compound 10

[0119] 1-(4-(Adamantylmethyl)phenyl)ethan-1-one

[0120]

[0121] Wherein, compound II is 1-(adamantylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0122] Yellow solid (40.7 mg, 76%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz,2H), 7.17 (d, J = 8.0 Hz, 2H), 2.59 (s, 3H), 2.43 (s, 2H), 2.00 – 1.90 (m,3H), 1.70 – 1.63 (m, 3H), 1.60 – 1.52 (m, 3H), 1.51 – 1.44 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 198.2, 144.5, 135.1, 130.8, 127.8, 51.3, 42.5, 37.0, 33.9,28.8, 26.7. IR (neat): 2903, 2846, 1682, 1606, 1356, 1266, 612 cm–1. HRMS (EI-QTOF) calcd. for C19H24O: 268.1822; found: 268.1824. Overall yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 95%; main product:byproduct (selectivity) = >99:1; GC-FID determination (temperature: 228 °C 3 min to 280 °C 3 min, heating at 10 °C / min); t R = 5.686 min (major product). Melting point 74.3-79.2 °C.

[0123] Compound 11

[0124] 1-(3-(Cyclohexylmethyl)phenyl)ethan-1-one

[0125]

[0126] Wherein, compound II is 1-(cyclohexylmethyl)-3-ethylbenzene, and the catalyst is catalyst I;

[0127] Yellow oily liquid (21.0 mg, 48%). 1H NMR (400 MHz, CDC13) δ 7.80 - 7.72 (m, 2H), 7.38 - 7.32 (m, 2H), 2.60 (s, 3H), 2.54 (d, J = 7.2 Hz, 2H), 1.73 - 1.62 (m, 5H), 1.58 - 1.48 (m, 1H), 1.30 - 1.07 (m, 3H), 1.01 - 0.88 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 198.7, 142.0, 137.1, 134.2, 128.9, 128.4, 126.0, 44.0, 39.9, 33.2, 26.8, 26.6, 26.4. IR (neat): 2923, 2850, 1685, 1444, 1357, 1267, 1190, 801, 694 cm-1. HRMS (EI-QTOF) calcd. for C15H20O: 216.1509; found: 216.1506. Total yield 1 H NMR (400 MHz, CDC13) 14 μL CH2Br2 as internal standard) = 68%; main product: side product (selectivity ratio) = 87:13; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min); t R = 12.599 min (side product), t R = 12.788 min (main product).

[0128] Compound 12

[0129] 1-(4-(3-methyl-n-butyl)phenyl)ethan-1-one

[0130]

[0131] wherein compound II is 1-(3-methyl-n-butyl)-4-ethylbenzene and the catalyst is catalyst I;

[0132] yellow oily liquid (22.6 mg, 64%). 1H NMR (400 MHz, CDC13) δ 7.88 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 2.72 - 2.63 (m, 2H), 2.58 (s, 3H), 1.61 - 1.44 (m, 3H), 0.94 (d, J = 6.4 Hz, 6H). 13 C NMR (101 MHz, CDC13) δ 198.0, 149.1, 134.9, 128.6, 128.5, 40.4, 33.9, 27.7, 26.6, 22.5. Total yield 1 H NMR (400 MHz, CDC13) 14 μL CH2Br2 as internal standard) = 66%; main product: side product (selectivity ratio) = 87:13; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min); t R = 10.446 min (side product), t R = 10.713 min (main product).

[0133] Compound 13

[0134] 1-(4-(3-ethyl-n-pentyl)phenyl)ethan-1-one

[0135]

[0136] wherein compound II is 1-(3-ethyl-n-pentyl)-4-ethylbenzene, and catalyst is catalyst I;

[0137] yellow oily liquid (22.0 mg, 50%). 1 H NMR (400 MHz, CDC13) δ 7.86 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 2.68 - 2.59 (m, 2H), 2.57 (s, 3H), 1.61 - 1.49 (m, 2H), 1.41 - 1.30 (m, 4H), 1.28 - 1.18 (m, 1H), 0.85 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 198.0, 149.4, 135.0, 128.7, 128.6, 40.1, 34.5,33.4, 26.7, 25.4, 10.9. IR (neat): 2960, 1682, 1606, 1459, 1357, 1266, 1181,954, 820 cm–1. HRMS (EI-QTOF) calcd. for C15H22O: 218.1665; found: 218.1662. Total yield ( 1 H NMR (400 MHz, CDCl3) 14μL CH2Br2 as internal standard) = 55%; main product: side product (selectivity ratio) = 91:9; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, temperature increase of 15 °C / min); t R = 12.037 min (side product), t R = 12.320 min (main product).

[0138] Compound 14

[0139] 1-(4-(3,3-dimethyl-n-butyl)phenyl)ethan-1-one

[0140]

[0141] wherein compound II is 1-(3,3-dimethyl-n-butyl)-4-ethylbenzene and catalyst is catalyst I;

[0142] yellowish oil liquid (22.6 mg, 57%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 2.66 – 2.51 (m, 5H), 1.55 – 1.45 (m, 2H),0.95 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 198.0, 149.7, 135.0, 128.7, 46.1,31.5, 30.7, 29.4, 26.7. Total yield ( 1H NMR (400 MHz, CDCl3) 14μL CH2Br2 as internal standard) = 73%; main product: side product (selectivity ratio) = 95:5; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, temperature ramp of 15 °C / min); t R = 10.730 min (side product), t R = 11.224 min (main product).

[0143] Compound 15

[0144] 1-(4-(2-Adamantyl ethyl)phenyl)ethan-1-one

[0145]

[0146] wherein compound II is 1-(2-adamantyl ethyl)-4-ethylbenzene, and catalyst is catalyst I;

[0147] Yellow solid (32.8 mg, 58%). 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz,2H), 7.26 (d, J = 8.0 Hz, 2H), 2.70 – 2.51 (m, 5H), 1.98 (s, 3H), 1.79 – 1.62(m, 6H), 1.55 (s, 6H), 1.42 – 1.33 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 198.1,150.0, 134.9, 128.7, 128.6, 46.6, 42.5, 37.3, 32.7, 29.5, 28.8, 26.7. IR(neat): 2902, 2845, 1765, 1679, 1603, 1449, 1357, 1263, 1098, 817 cm–1. HRMS(EI-QTOF) calcd. for C20H26O: 282.1978; found: 282.1981. Total yield ( 1 H NMR (400 MHz, CDCl3) 14μL CH2Br2 as internal standard) = 73%; main product: side product (selectivity ratio) = 95:5; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, temperature ramp of 15 °C / min); t R = 16.381 min (side product), tR = 16.926 min (main product).

[0148] Compound 16

[0149] 1-(4-(4-methyl-n-pentyl)phenyl)ethan-1-one

[0150]

[0151] wherein compound II is 1-(4-methyl-n-pentyl)-4-ethylbenzene and the catalyst is catalyst I;

[0152] Yellow solid (19.8 mg, 51%). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz,2H), 7.27 (d, J = 8.0 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.59 (s, 3H), 1.72 –1.50 (m, 4H), 1.29 – 1.17 (m, 1H), 0.87 (d, J = 6.4 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 198.0, 148.9, 134.9, 128.6, 128.5, 38.6, 36.3, 29.0, 27.9, 26.6, 22.6. IR (neat): 2956, 1765, 1684, 1606, 1464, 1360, 1264, 1055, 799 cm–1.HRMS (EI-QTOF) calcd. for C14H20O: 204.1509; found: 204.1506. Total yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 69%; main product: side product (selectivity ratio) = 77:23; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min); t R = 11.388 min (side product), t R = 11.488 min (main product).

[0153] Compound 17

[0154] 1-(4-(4,4-dimethyl-n-pentyl)phenyl)ethan-1-one

[0155]

[0156] Wherein, compound II is 1-(4,4-dimethyl-n-pentyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0157] Yellow solid (21.4 mg, 56%). 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.59 (s, 3H), 1.65 –1.55 (m, 2H), 1.27 – 1.17 (m, 2H), 0.87 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ198.1, 149.0, 135.0, 128.7, 128.6, 43.9, 37.0, 30.4, 29.5, 26.7, 26.4. IR(neat): 2949, 1682, 1606, 1470, 1359, 1266, 1181, 955, 844, 596. HRMS (EI-QTOF) calcd. for C15H22O: 218.1665; found: 218.167. Overall yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 59%; main product: by-product (selectivity) = 76:24; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, heating at 15 °C / min); t R = 11.537 min (byproduct), t R =11.630 min (main product).

[0158] Example 2:

[0159] Table 2

[0160] .

[0161] As shown in Table 2, when the present invention is applied to some substrates containing electron-rich groups, the electron-rich groups can better stabilize free radicals, thereby reversing the regioselectivity of the reaction. However, for the oxidation of benzyl hydrocarbons with less steric hindrance, the NHMI catalyst still shows a higher tendency than NHPI.

[0162] The compound characterization results obtained in Table 2 are as follows:

[0163] Compound 18

[0164] 1-(4-(Cyclopropylmethyl)phenyl)ethan-1-one

[0165]

[0166] wherein compound II is 1-(cyclopropylmethyl)-4-ethylbenzene and the catalyst is catalyst I;

[0167] Yellow oily liquid (10.7 mg, 34%). 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 2.61 (s, 2H), 2.59 (s, 3H), 1.07 – 0.92 (m, 1H), 0.63 – 0.52 (m, 2H), 0.26 – 0.18 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 198.1, 148.2, 135.2, 128.7, 128.6, 40.5, 26.7, 11.7, 4.9. IR (neat): 2924, 1682, 1606, 1358, 1267, 1018, 823 cm–1. HRMS (EI-QTOF) calcd. for C12H14O: 174.1039; found: 174.1036. Total yield ( 1 H NMR (400 MHz, CDCl3) 14 μL CH2Br2 as internal standard) = 51%; main product: side product (selectivity ratio) = 34:66; regioselectivity determined by 1 H NMR (400 MHz, CDCl3).

[0168] Compound 19

[0169] 1-(4-(Phenylmethyl)phenyl)ethan-1-one

[0170]

[0171] wherein compound II is 1-(phenylmethyl)-4-ethylbenzene and the catalyst is catalyst I;

[0172] Yellow oily liquid (26.9 mg). 1H NMR (400 MHz, CDC13) δ 7.91 (d, J = 8.4 Hz, 2H), 7.39 - 7.12 (m, 7H), 4.06 (s, 2H), 2.60 (s, 3H). 13 C NMR (101 MHz, CDC13) δ 198.0, 147.0, 140.2, 135.4, 129.2, 129.1, 128.8, 128.8, 126.5, 42.0, 26.7. Total yield 1 H NMR (400 MHz, CDC13) 14 μL CH2Br2 as internal standard) = 67%; main product: side product (selectivity ratio) = 44:56; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min); t R = 12.975 min (side product), t R = 12.815 min (main product).

[0173] Compound 20

[0174] 1-(4-( (4-methoxyphenyl)methyl)phenyl)ethan-1-one

[0175]

[0176] wherein compound II is 1-( (4-methoxyphenyl)methyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0177] Colorless oily liquid (20.0 mg, 49%). 1 H NMR (400 MHz, CDC13) δ 7.82 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). 13 CNMR (101 MHz, CDC13) δ 195.4, 163.0, 148.8, 135.7, 132.5, 130.5, 130.1, 127.7, 113.5, 55.5, 29.0, 15.3. Total yield 1H NMR (400 MHz, CDC13) 14 pL CH2Br2 as internal standard) = 52%; main product: side product (selectivity ratio) = 5:95; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min);

[0178] Compound 21

[0179] 1 -(4-( (4-trifluoromethylphenyl)methyl)phenyl)ethan-1 -one

[0180]

[0181] wherein compound II is 1 -( (4-trifluoromethylphenyl)methyl)-4-ethylbenzene and catalyst is catalyst I;

[0182] Yellow oily liquid (9.6 mg, 20%). 1 H NMR (400 MHz, CDC13) δ 7.93 - 7.81 (m, 2H), 7.78 - 7.73 (m, 4H), 7.38 - 7.29 (m, 2H), 2.75 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 195.3, 150.3, 141.1, 134.3, 133.7, 133.3, 130.5, 130.0, 128.1, 125.4, 125.3, 125.3, 125.2, 125.1, 122.4, 29.0, 15.2.19F NMR (377 MHz, CDC13) δ -63.3. Total yield ( 1 H NMR (400 MHz, CDC13) 14 pL CH2Br2 as internal standard) = 52%; main product: side product (selectivity ratio) = 5:95; GC-FID determination (temperature: 60 °C 2 min to 280 °C 2 min, ramping at 15 °C / min);

[0183] Example 3: Comparison of catalytic conditions

[0184] (1) Using compound I as substrate, the oxidation effect of different catalysts was tested according to the reaction condition of Example I. As can be seen from Table 3, compared with the traditional NHPI type catalyst, the newly developed large steric hindrance NHMI type catalyst is more excellent in regioselectivity for the same substrate, and the catalyst solves the problem of over-oxidation often occurring in the NHPI catalyst.

[0185]

[0186] Table 3

[0187]

[0188] Note: "Combined yield" refers to the percentage of the total material in the reaction solution (obtained from crude nuclear magnetic spectrum) of the main product and by-product; "over-oxidation" refers to the percentage of the total material in the reaction solution (obtained from crude nuclear magnetic spectrum) of the two benzyl positions being oxidized; the regioselectivity of the reaction is obtained by GC-FID detection before column chromatography separation of the reaction solution.

[0189] (2) Solvent comparison

[0190]

[0191] Using the solvents shown in the following table, 8 mL each, the reaction results are shown in Table 4, according to the operation of Reference Example 1, replacing the anode electrode with a reticular glassy carbon electrode (RVC), and the current is 1.0 mA.

[0192] Table 4

[0193] .

Claims

1. A method for preparing compound I, characterized in that: The method comprises the following steps: in a solvent, in the presence of a catalyst and an alkaline agent, subjecting compound II to an electrolytic oxidation reaction to generate compound I; Where R is C1-C 10 Alkyl or n is 0, 1, 2 or 3; R1 is C4-C 12 Cycloalkyl; The catalyst is wherein T is independently phenyl or tert-butyl; m is 0, 1 or 2; The solvent is a halogenated alkane solvent, a ketone solvent or a nitrile solvent; The alkaline agent is pyridine substituted by one or more C1-C4 alkyl groups.

2. The preparation method according to claim 1, wherein It meets one or more of the following conditions: (1) The solvent is 1,2-dichloroethane, acetone or acetonitrile; (2) the C1-C4 alkyl group is a methyl group; (3) The electrolytic oxidation reaction is carried out under oxygen conditions; (4) The electrolytic oxidation reaction is carried out in the presence of an electrolyte; (5) The reaction device of the electrolytic oxidation reaction includes an anode electrode, a cathode electrode and an electrolyte; (6) The reaction current of the electrolytic oxidation reaction is 0.5 to 1.5 mA; (7) The voltage of the electrolytic oxidation reaction does not exceed 2.5V; (8) The reaction temperature of the electrolytic oxidation reaction is 21 to 50° C.; (9) The electrolytic oxidation reaction further comprises the following steps: after the reaction is completed, adding an ester solvent, washing, concentrating, and purifying by silica gel column chromatography to obtain compound I.

3. The preparation method according to claim 2, wherein It meets one or more of the following conditions: (1) The solvent is 1,2-dichloroethane; (2) The alkaline reagent is 2,6-lutidine; (3) The electrolytic oxidation reaction is carried out in an oxygen atmosphere of 1 atm; (4) The anode electrode is a carbon felt electrode, a carbon plate, a platinum electrode or a mesh glassy carbon electrode; (5) The cathode electrode is a platinum sheet electrode, a carbon felt electrode, a carbon plate or a mesh glassy carbon electrode; (6) The reaction current of the electrolytic oxidation reaction is 0.5 mA; (7) The voltage of the electrolytic oxidation reaction is 2.0 to 2.5 V; (8) The reaction temperature of the electrolytic oxidation reaction is 30°C.

4. The preparation method according to claim 2, wherein The voltage of the electrolytic oxidation reaction is 2.3V or 2.5V.

5. The preparation method according to claim 2, wherein It meets one or more of the following conditions: (1) The electrolyte is a buffer salt or an organic ammonium salt; (2) The molar volume ratio of the electrolyte to the solvent is 0.05-0.4 mol / L; (3) The anode electrode is immersed in the solution for at least 1 cm; (4) the concentration of the compound II in the solvent is 0.01-0.05 mmol / mL; (5) The molar ratio of the compound II to the catalyst is 1:(0.1-0.5); (6) The molar ratio of the compound II to the electrolyte is 1:(2-5); (7) The molar ratio of the compound II to the alkaline reagent is 1:(0.5-5); (8) The anode electrode is a carbon felt electrode; (9) The cathode electrode is a platinum electrode; (10) The electrolytic oxidation reaction comprises the following reaction steps: in the presence of oxygen, the compound II, the catalyst, the electrolyte and the alkaline reagent are mixed and dissolved in the solvent, and then an electrolytic oxidation reaction is carried out; (11) The raw materials of the electrolytic oxidation reaction are the compound II, the catalyst, oxygen, 2,6-lutidine tetrafluoroboric acid, 2,6-lutidine and dichloroethane; wherein the catalyst is 6. The preparation method according to claim 2, wherein It meets one or more of the following conditions: (1) The electrolyte is [PyH]BF4, [2,6-lutH]BF4, [2,4,6-ColH]BF4, n Bu4ClO4, n Bu4NCl or n Bu4NBF4; (2) the molar volume ratio of the electrolyte to the solvent is 0.1 mol / L; (3) the concentration of the compound II in the solvent is 0.025 mmol / mL; (4) the molar ratio of the compound II to the catalyst is 1:0.2; (5) The molar ratio of the compound II to the electrolyte is 1:4; (6) The molar ratio of the compound II to the alkaline reagent is 1:0.

5.

7. The preparation method according to claim 5, wherein The electrolyte is [2,6-lutH]BF4.

8. The preparation method according to any one of claims 1 to 7, characterized in that The C1-C 10 Alkyl is a straight or branched C1-C 10 alkyl.

9. The preparation method according to claim 8, wherein The C1-C 10 The alkyl group is a linear or branched C1-C6 alkyl group.

10. The preparation method according to claim 8, characterized in that The C1-C 10 Alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 11. The preparation method according to any one of claims 1 to 7, characterized in that: The C4-C 12 Cycloalkyl is C4-C 12 Monocyclic, bicyclic or bridged cycloalkyl.

12. The preparation method according to claim 11, characterized in that The C4-C 12 Cycloalkyl is 13. The preparation method according to any one of claims 1 to 7, characterized in that: The compound I is 14. The preparation method according to any one of claims 1 to 7, characterized in that: The compound II is 15. The preparation method according to any one of claims 1 to 7, characterized in that: The catalyst is 16. A method for preparing compound III, characterized in that: The method comprises the following steps: in a solvent, in the presence of a catalyst and an alkaline reagent, subjecting compound IV to an electrolytic oxidation reaction to generate compound III; Wherein R2 is cyclopropyl, phenyl or one or more R 2-1 Substituted phenyl; R 2-1 is C1-C4 alkyl which is unsubstituted or substituted by one or more halogens, or C1-C4 alkoxy which is unsubstituted or substituted by one or more halogens; The catalyst is wherein T is independently phenyl or tert-butyl; m is 0, 1 or 2; The solvent is a halogenated alkane solvent, a ketone solvent or a nitrile solvent; The alkaline agent is pyridine substituted by one or more C1-C4 alkyl groups.

17. The method for preparing compound III according to claim 16, wherein: The solvent, catalyst, alkaline reagent and electrolytic oxidation reaction are as described in any one of claims 2 to 7 and 15.

18. The preparation method according to claim 16, wherein It meets one or more of the following conditions: (1) The halogen is independently F, Cl, Br or I; (2) The compound III is any one of the following: (3) Compound IV is any one of the following:

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