Method for selective electrochemical oxidation of benzylic carbon-hydrogen bond

Abstract

Disclosed in the present invention is a method for the selective electrochemical oxidation of a benzylic carbon-hydrogen bond. Provided in the present invention is a preparation method for compound I. The preparation method comprises the following step: in a solvent, subjecting compound II to an electrolytic oxidation reaction in the presence of a catalyst and an alkaline reagent, so as to generate compound I. The preparation method provided by the present invention combines a large-steric-hindrance hydrogen atom transfer reagent, i.e., an N-hydroxy maleoyl hydroxylamine analogue, with organic electrosynthesis for the first time, thereby signifiantly improving the regioselectivity of the reaction.

Description

An electrochemical oxidation method for selective benzyl C-H bonds

[0001] This application claims priority to Chinese patent application 2024112082275, filed on August 30, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to an electrochemical oxidation method for selective benzyl C-H bonds. Background Technology

[0003] Electrochemical oxidation reactions offer advantages such as mild conditions, low pollution, and convenient operation. Unlike traditional thermochemical reactions, electrochemical oxidation reactions often require the generation of free radicals through a base-promoted PCET process on the electrode surface, which then leads to hydrogen atom transfer reactions to produce intermediates such as benzyl radicals (10.1038 / nature17431; 10.1248 / cpb.35.1372). After the free radicals are generated, they are captured by oxygen to obtain the product.

[0004] Poor regioselectivity has long been a challenge in electrochemical oxidation reactions. In traditional benzylic electrochemical oxidation reactions, N-hydroxyphthalyl hydroxylamine (NHPI) has difficulty distinguishing benzylic C-H bonds with similar charges but different steric hindrances, and its high reactivity easily leads to over-oxidation of the substrate, thus limiting its application in reactions requiring high selectivity.

[0005] This invention is the first to combine sterically hindered hydrogen atom transfer reagent N-hydroxymaleylhydroxylamine (NHMI) analogues with organic electrosynthesis. Under electrochemical conditions, by controlling the reaction selectivity through catalyst structure, the regioselectivity of the reaction is significantly improved compared with that of NHPI and its analogues. This innovative method effectively solves the problem of poor regioselectivity in the field of electrochemical oxidation and provides a new solution for highly selective reactions. Summary of the Invention

[0006] The technical problem solved by this invention is to address the shortcomings of existing technologies by providing a method for highly selective oxidation of benzyl C-H bonds under electrochemical conditions. This invention provides a selective electrochemical oxidation method for benzyl C-H bonds. The method provided by this invention achieves high regioselectivity in the field of electrochemical oxidation.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a method for preparing compound I, comprising the following steps: in a solvent, in the presence of a catalyst and a basic reagent, compound II is subjected to an electrolytic oxidation reaction to generate compound I;

[0009] Where R is C1-C 10 alkyl or

[0010] n is 0, 1, 2, or 3; R1 is C4-C 12 cycloalkyl;

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

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

[0013] In some embodiments of the present invention, the solvent may be a haloalkane solvent, a ketone solvent, or a nitrile solvent, such as 1,2-dichloroethane, acetone, or acetonitrile; preferably 1,2-dichloroethane.

[0014] In some embodiments of the present invention, 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 invention, the electrolytic oxidation reaction is carried out under oxygen conditions, for example, in an oxygen atmosphere of 1 atm.

[0016] In some embodiments of the invention, the oxidation reaction is carried out in the presence of an electrolyte. The electrolyte may be a buffer salt or an organic ammonium salt, such as [PyH]BF4, [2,6-lutH]BF4, [2,4,6-ColH]BF4, etc. n Bu4ClO4、 n Bu4NCl or n Bu4NBF4, preferably [2,6-lutH]BF4.

[0017] In some embodiments of the present invention, the reaction apparatus for the electrolytic oxidation reaction includes an anode electrode, a cathode electrode and an electrolyte; the anode electrode may be a carbon felt electrode, a carbon plate, a platinum electrode or a glassy carbon mesh (RVC) electrode (preferably a carbon felt electrode); the cathode electrode is preferably a platinum sheet electrode, a carbon felt electrode, a carbon plate or a glassy carbon mesh (RVC) electrode, and is preferably a platinum sheet electrode.

[0018] In some embodiments of the present invention, 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 invention, the reaction current of the electrolytic oxidation reaction is 0.5 to 1.5 mA; preferably 0.5 mA.

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

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

[0022] In some embodiments of the present invention, the electrolytic oxidation reaction process is monitored using conventional monitoring methods for such reactions in the art, such as TLC. Preferably, the reaction endpoint is defined as the complete conversion of compound II or the cessation of compound I formation. The electrolytic oxidation reaction time can be 24–36 hours; preferably 30 hours.

[0023] In some embodiments of the present invention, 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 invention, the concentration of compound II in the solvent may be 0.01-0.05 mmol / mL, preferably 0.025 mmol / mL.

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

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

[0027] In some embodiments of the present invention, the molar ratio of compound II to the alkaline reagent may be 1:(0.5-5), preferably 1:0.5.

[0028] In some embodiments of the present invention, the electrolytic oxidation reaction includes 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.

[0029] In some embodiments of the present invention, the electrolytic oxidation reaction further includes the following steps: after the reaction is completed, an ester solvent (e.g., ethyl acetate) is added, followed by washing (e.g., washing with water), concentration, and purification by silica gel column chromatography to obtain compound I; the silica gel column chromatography can be performed using conventional operations and mobile phase ratios in the art, such as elution with ethyl acetate / petroleum ether = 2:98.

[0030] In some embodiments of the present invention, the C1-C 10 Alkyl groups are straight-chain or branched C1-C 10 Alkyl; for example, straight-chain or branched C1-C8 alkyl groups (e.g., straight-chain or branched C4-C8 alkyl groups); preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,

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

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

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

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

[0035] In some embodiments of the present invention, the raw materials for the electrolytic oxidation reaction are compound II, the catalyst, oxygen, 2,6-dimethylpyridine tetrafluoroboric acid, 2,6-dimethylpyridine, and dichloroethane; wherein, the catalyst is...

[0036] The present invention also provides a method for preparing compound III, which includes the following steps: in a solvent, in the presence of a catalyst and a basic reagent, compound IV is subjected to an electrolytic oxidation reaction to generate compound III;

[0037] Wherein, R2 is cyclopropyl, phenyl, or is replaced by one or more R 2-1 Substituted phenyl; R 2-1 It is an unsubstituted or substituted C1-C4 alkyl or an unsubstituted or substituted C1-C4 alkoxy group;

[0038] The solvent, catalyst, basic reagent, and electrolytic oxidation reaction are as described above.

[0039] In some embodiments of the invention, the halogen is independently F, Cl, Br or I.

[0040] In some embodiments of the present invention, compound III is any one of the following:

[0041] In some embodiments of the present invention, compound IV is any one of the following:

[0042] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0043] The reagents and raw materials used in this invention are all commercially available.

[0044] The positive and progressive effects of this invention are as follows: This invention is the first to combine N-hydroxymaleylhydroxylamine (NHMI) derivatives with organic electrosynthesis, which improves the regioselectivity of the reaction and reduces peroxidation. Detailed Implementation

[0045] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0046] 1. Catalyst Synthesis:

[0047] For the synthesis of N-hydroxymaleic hydroxylamine, please refer to (T. Kato, K. Maruoka, Angewandte Chemie International Edition 2020, 59, 14261–14264);

[0048] The synthesis route for catalyst I is as follows:

[0049] 2. Construction of the electrochemical device

[0050] Take a 25 mL three-necked flask, punch holes in the rubber stopper to allow electrodes to pass through while ensuring an airtight seal. The anode is a carbon felt electrode (10 x 3 x 25 mm), and the cathode is a platinum sheet electrode (10 x 10 mm). Then, add the substrate (0.2 mmol, 1 equiv.), electrolyte (2,6-dimethylpyridine tetrafluoroborate, 0.1 M, 0.8 mmol), and sterically hindered catalyst (0.04 mmol, 0.2 equiv.) to the flask. After addition, add a three-way stopcock to the three-necked flask and evacuate the oxygen supply. Then, add 2,6-dimethylpyridine (0.5 equiv., 0.1 mmol, 10.7 mg) and solvent 1,2-dichloroethane (8 mL). After addition, place the reaction system in a 30 °C oil bath and stir at 800 rpm for 15 min until all solids are dissolved.

[0051] 3. Electrolysis parameters:

[0052] Connect the anode and cathode to a DC power supply 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 submerged in the solution, while the initial voltage is around 2.3 V, and electrolyze for 30 hours.

[0053] 4. Reaction processing:

[0054] Dilute brine and a large amount of ethyl acetate were added to the system for extraction. The organic phase obtained by extraction was dried, concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 98:2). The main product was a sterically hindered oxidation product, which turned yellow or orange when colored with phenylhydrazine solution.

[0055] Regional selectivity determination:

[0056] Take a small amount of the extracted reaction solution, dilute it to an appropriate concentration, and use a GC-FID detector to detect the regioselectivity. The specific method is as follows:

[0057] Column: Agilent HP-5ms Ultra Inert 0℃–325℃ (350℃): 30m x 250μm x 0.25μm.

[0058] Inlet: 260℃, split injection, split ratio: 20 / 1, carrier gas flow rate: 2 mL / min (He), pressure: 21.844 psi, injection volume: 1 μL (using an autosampler).

[0059] Column oven: 60℃ (hold for 2 min) increase to 280℃ (hold for 2 min) at a rate of 15℃ / min.

[0060] Detector: 280℃, H2: 30mL / min, air: 400mL / min, tail gas (N2): 25mL / min.

[0061] Example 1:

[0062] In an oxygen-rich environment, compound II (0.2 mmol, 1.0 equivalent), catalyst (20 mol%, 0.04 mmol, 0.2 equivalent), and 2,6-dimethylpyridine tetrafluoroboronic acid (LutHBF4) (0.8 mmol, 4.0 equivalent, 0.1 M) were added to a three-necked flask. Subsequently, at 30 °C, 2,6-dimethylpyridine (0.1 mmol, 0.5 equivalent) and dichloroethane (8 mL) were added to the mixture through a diaphragm. Before electrolysis, the mixture was stirred for 15 minutes to dissolve the electrolyte. The mixture was then electrolyzed for 30 hours (0.5 mA, <2.5 V). After the reaction, the mixture was diluted with ethyl acetate and washed with water to remove the electrolyte, then concentrated under vacuum. The residue was further purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether = 2:98) to give compound I as the main product and compound III as the byproduct.

[0063] The following compounds were prepared according to the synthetic conditions of Exercise 1:

[0064] Table 1

[0065] As can be seen from Table 1, the reaction exhibits good reactivity to substrates with different steric hindrance groups. Furthermore, compared to NHPI, the NHMI catalyst demonstrates superior regioselectivity and higher selectivity for sterically hindrance benzyl hydrocarbons.

[0066] The characterization results of the compounds obtained are shown in Table 1:

[0067] Compound 1

[0068] 1-(4-(cyclohexylmethyl)phenyl)ethyl-1-one (1a)

[0069] Compound II is 1-(cyclohexylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0070] Yellow oily substance (27.2 mg, 63%). 1 H NMR(400MHz, CDCl3) δ7.87(d,J=8.5Hz,2H),7.22(d,J=8.4Hz,2H),2.58(s,3H), 2.54(d,J=7.2Hz,2H),1.90–1.48(m,7H),1.23–1.13(m,2H),1.01–0.94(m,2H). 13 C NMR (101MHz, 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 ( 1¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 77%; main product:by product (selectivity ratio) = 87:13; GC-FID determination (temperature: 180℃ for 3 min to 280℃ for 2 min, increasing at 10℃ / min); t R = 5.640 min (byproducts), t R = 5.939 min (main product).

[0071] Compound 2

[0072] 1-(4-(cyclobutylmethyl)phenyl)ethyl-1-one

[0073] Compound II is 1-(cyclobutylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0074] Colorless oil (17.5 mg, 45%). 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),2.75(d,J=7.2Hz,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 CNMR (101MHz, CDCl3) δ 198.1, 147.3, 135.1, 128.8, 128.6, 43.1, 37.1, 28.3, 26.7, 18.5. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 58% Main product:by-product (selectivity ratio) = 62:38 The selectivity of this region is determined by... 1 Identified by H NMR (400MHz, CDCl3).

[0075] Compound 3

[0076] 1-(4-(cyclopentylmethyl)phenyl)ethyl-1-one

[0077] Compound II is 1-(cyclopentylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0078] Yellow oily substance (23.9 mg, 58%). 1H NMR (400MHz, CDCl3) δ7.87 (d, J = 8.4Hz, 2H), 7.26 (d, J = 8.4Hz, 2H), 2.67 (d, J = 7. 6Hz,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 (101MHz, CDCl3) δ 198.1, 148.4, 135.0, 129.1, 128.5, 42.2, 41.8, 32.6, 26.7, 25.0. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 54%; main product:by product (selectivity ratio) = 76:24; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 12.126 min (byproducts), t R = 12.305 min (main product).

[0079] Compound 4

[0080] 1-(4-(cycloheptylmethyl)phenyl)ethyl-1-one

[0081] Compound II is 1-(cycloheptylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0082] Yellow oily substance (23.5 mg, 51%). 1 H NMR(400MHz, CDCl3) δ7.87(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,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). 13 C16H22O NMR (101MHz, 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, 800cm–1. HRMS (EI-QTOF) calcd. for C16H22O: 230.1665; found: 230.1663. Total yield ( 1¹H NMR (400MHz, CDCl₃) with 14 μL CH₂Br₂ as internal standard = 68%; main product:by product (selectivity ratio) = 89:11; GC-FID determination (temperature: 196℃ for 2 min to 280℃ for 2 min, increasing at 10℃ / min); t R = 5.527 min (byproducts), t R = 5.834 min (main product).

[0083] Compound 5

[0084] 4-Cyclohexylacetophenone

[0085] Compound II is 1-cyclohexyl-4-ethylbenzene, and the catalyst is catalyst I;

[0086] Yellow oily substance (24.3 mg, 60%). 1 H NMR (400MHz, CDCl3) δ7.89 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 2.58 (s, 3H), 1.93–1.71 (m, 5H), 1.53–1.16 (m, 6H). 13 C NMR (101MHz, CDCl3) δ 198.0, 153.9, 135.2, 128.7, 127.2, 44.8, 34.2, 26.8, 26.7, 26.1. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 61%; main product:by product (selectivity ratio) => 99:1; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 12.244 min (main product).

[0087] Compound 6

[0088] 4-n-Pentylacetophenone

[0089] Compound II is 1-(n-pentyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0090] Colorless oily liquid (17.6 mg, 49%). 1H NMR (400MHz, CDCl3) δ7.88(d,J=8.6Hz,2H),7.26(d,J=8.6Hz,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=6.8Hz,3H). 13 C NMR (101MHz, 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 ¹H NMR (400MHz, CDCl₃) with 14 μL CH₂Br₂ as internal standard = 64%; main product:by product (selectivity ratio) = 80:20; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 10.904 min (byproducts), t R = 11.000 min (main product).

[0091] Compound 7

[0092] 1-(4-(isopropylmethyl)phenyl)ethyl-1-one

[0093] Compound II is 1-(isopropylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0094] Yellow oily liquid (27.4 mg, 65%). 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),2.59(s,3H),2.53(d,J=7.2Hz,2H),1.96–1.83(m,1H),0.91(d,J=6.8Hz,6H). 13 C NMR (101MHz, CDCl3) δ 198.1, 147.7, 135.1, 129.4, 128.4, 45.5, 30.2, 26.7, 22.5. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) with 14 μL CH₂Br₂ as internal standard) = 86%; main product:by product (selectivity ratio) = 88:12; GC-FID determination (temperature: 112℃ for 3 min to 172℃ for 3 min, increasing at 10℃ / min); t R = 7.508 min (byproducts), t R = 7.765 min (main product).

[0095] Compound 8

[0096] 1-(2-Ethylbutylphenyl)ethyl-1-one

[0097] Compound II is 1-(2-ethylbutyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0098] Yellow oily liquid (23.1 mg, 61%). 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),2.64–2.51(m,5H),1.54(hept,J=6.0Hz,1H),1.33–1.25(m,4H),0.87(t,J=7.4Hz,6H). 13 C NMR (101MHz, 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 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 71%; main product:by product (selectivity ratio) = 92:8; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 10.929 min (byproducts), t R = 11.470 min (main product).

[0099] Compound 9

[0100] 1-(4-(tert-butylmethyl)phenyl)ethyl-1-one

[0101] Compound II is 1-(tert-butylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0102] Yellow oily liquid (31.6 mg, 83%). 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 2.67 (s, 3H), 2.63 (s, 2H), 0.99 (s, 9H). 13 C NMR (101MHz, CDCl3) δ 198.2, 145.8, 135.1, 130.7, 127.9, 50.3, 32.1, 29.5, 26.7. Total yield ( 1¹H NMR (400MHz, CDCl₃) with 14 μL CH₂Br₂ as internal standard) = 97%; main product:by product (selectivity ratio) => 99:1; GC-FID determination (temperature: 130℃ for 3 min to 190℃ for 3 min, increasing at 10℃ / min); t R = 6.671 min (main product).

[0103] Compound 10

[0104] 1-(4-(adamantylmethyl)phenyl)ethyl-1-one

[0105] Compound II is 1-(adamantylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0106] Yellow solid (40.7 mg, 76%). 1 H NMR(400MHz, CDCl3) δ7.86(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,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 C19H24O NMR (101MHz, 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. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) with 14 μL CH₂Br₂ as internal standard = 95%; main product:by product (selectivity ratio) => 99:1; GC-FID determination (temperature: 228℃ for 3 min to 280℃ for 3 min, increasing at 10℃ / min); t R = 5.686 min (main product). Melting point 74.3-79.2℃.

[0107] Compound 11

[0108] 1-(3-(cyclohexylmethyl)phenyl)ethyl-1-one

[0109] Compound II is 1-(cyclohexylmethyl)-3-ethylbenzene, and the catalyst is catalyst I;

[0110] Yellow oily liquid (21.0 mg, 48%). 1 H NMR (400MHz, CDCl3) δ7.80–7.72(m,2H),7.38–7.32(m,2H),2.60(s,3H),2.54(d,J=7. 2Hz,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 C15H2O NMR (101MHz, CDCl3) 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 C15H2O: 216.1509; found: 216.1506. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 68%; main product:by product (selectivity ratio) = 87:13; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 12.599 min (byproducts), t R = 12.788 min (main product).

[0111] Compound 12

[0112] 1-(4-(3-methyl-n-butyl)phenyl)ethyl-1-one

[0113] Compound II is 1-(3-methyl-n-butyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0114] Yellow oily liquid (22.6 mg, 64%). 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),2.72–2.63(m,2H),2.58(s,3H),1.61–1.44(m,3H),0.94(d,J=6.4Hz,6H). 13C NMR (101MHz, CDCl3) δ 198.0, 149.1, 134.9, 128.6, 128.5, 40.4, 33.9, 27.7, 26.6, 22.5. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 66%; main product:by product (selectivity ratio) = 87:13; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 10.446 min (byproducts), t R = 10.713 min (main product).

[0115] Compound 13

[0116] 1-(4-(3-ethylpentyl)phenyl)ethyl-1-one

[0117] Compound II is 1-(3-ethylpentyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0118] Yellow oily liquid (22.0 mg, 50%). 1 H NMR(400MHz, CDCl3)δ7.86(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),2.68–2.59(m,2H),2.5 7(s,3H),1.61–1.49(m,2H),1.41–1.30(m,4H),1.28–1.18(m,1H),0.85(t,J=7.4Hz,6H). 13 CNMR (101MHz, 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 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard = 55%; main product:by product (selectivity ratio) = 91:9; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 12.037 min (byproducts), t R = 12.320 min (main product).

[0119] Compound 14

[0120] 1-(4-(3,3-dimethyl-n-butyl)phenyl)ethyl-1-one

[0121] Compound II is 1-(3,3-dimethyl-n-butyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0122] Yellow oily liquid (22.6 mg, 57%). 1 H NMR (400MHz, CDCl3) δ7.86 (d, J = 8.4Hz, 2H), 7.25 (d, J = 8.4Hz, 2H), 2.66–2.51 (m, 5H), 1.55–1.45 (m, 2H), 0.95 (s, 9H). 13 C NMR (101MHz, CDCl3) δ 198.0, 149.7, 135.0, 128.7, 46.1, 31.5, 30.7, 29.4, 26.7. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 73%; main product:by product (selectivity ratio) = 95:5; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 10.730 min (byproducts), t R = 11.224 min (main product).

[0123] Compound 15

[0124] 1-(4-(2-adamantylethyl)phenyl)ethyl-1-one

[0125] Compound II is 1-(2-adamantylethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0126] Yellow solid (32.8 mg, 58%). 1 H NMR(400MHz, CDCl3) δ7.87(d,J=8.0Hz,2H),7.26(d,J=8.0Hz,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). 13C NMR (101MHz, 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 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 67%; main product:by product (selectivity ratio) = 91:9; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 16.381 min (byproducts), t R = 16.926 min (main product).

[0127] Compound 16

[0128] 1-(4-(4-methyl-n-pentyl)phenyl)ethyl-1-one

[0129] Compound II is 1-(4-methyl-n-pentyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0130] Yellow solid (19.8 mg, 51%). 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,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=6.4Hz,6H). 13 C14H2O NMR (101MHz, 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 C14H2O: 204.1509; found: 204.1506. Total yield ( 1¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 69%; main product:by product (selectivity ratio) = 77:23; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 11.388 min (byproducts), t R = 11.488 min (main product).

[0131] Compound 17

[0132] 1-(4-(4,4-dimethyl-n-pentyl)phenyl)ethyl-1-one

[0133] Compound II is 1-(4,4-dimethyl-n-pentyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0134] Yellow solid (21.4 mg, 56%). 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.4Hz,2H),7.27(d,J=8.4Hz,2H),2.63(t,J =7.6Hz,2H),2.59(s,3H),1.65–1.55(m,2H),1.27–1.17(m,2H),0.87(s,9H). 13 C15H22O NMR (101MHz, CDCl3) δ 198.1, 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. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 59%; main product:by product (selectivity ratio) = 76:24; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 11.537 min (byproducts), t R = 11.630 min (main product).

[0135] Example 2:

[0136] Table 2

[0137] As shown in Table 2, when the present invention is applied to substrates containing electron-rich groups, the regioselectivity of the reaction is reversed because electron-rich groups can better stabilize free radicals. However, for the oxidation of benzyl hydrocarbons with low steric hindrance, the NHMI catalyst still shows a higher tendency than NHPI.

[0138] The characterization results of the compounds obtained are shown in Table 2:

[0139] Compound 18

[0140] 1-(4-(cyclopropylmethyl)phenyl)ethyl-1-one

[0141] Compound II is 1-(cyclopropylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0142] Yellow oily liquid (10.7 mg, 34%). 1 H NMR(400MHz, CDCl3) δ7.90(d,J=8.4Hz,2H),7.35(d,J=8.4Hz,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 C12H14O NMR (101MHz, 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 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 51%; main product:by product (selectivity ratio) = 34:66; regioselectivity is determined by... 1 Identified by H NMR (400MHz, CDCl3).

[0143] Compound 19

[0144] 1-(4-(phenylmethyl)phenyl)ethyl-1-one

[0145] Compound II is 1-(phenylmethyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0146] Yellow oily liquid (26.9 mg). 1H NMR (400MHz, CDCl3) δ7.91 (d, J = 8.4Hz, 2H), 7.39–7.12 (m, 7H), 4.06 (s, 2H), 2.60 (s, 3H). 13 C NMR (101MHz, CDCl3) 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 ¹H NMR (400MHz, CDCl₃) 14 μL CH₂Br₂ as internal standard) = 67%; main product:by product (selectivity ratio) = 44:56; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, increasing at 15℃ / min); t R = 12.975 min (byproducts), t R = 12.815 min (main product).

[0147] Compound 20

[0148] 1-(4-((4-methoxyphenyl)methyl)phenyl)ethyl-1-one

[0149] Compound II is 1-((4-methoxyphenyl)methyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0150] Colorless oily liquid (20.0 mg, 49%). 1 H NMR (400MHz, CDCl3) δ7.82(d,J=8.8Hz,2H),7.70(d,J=8.4Hz,2H),7.30(d,J=8.4Hz, 2H), 6.96 (d, J = 8.8Hz, 2H), 3.89 (s, 3H), 2.73 (q, J = 7.6Hz, 2H), 1.28 (t, J = 7.6Hz, 3H). 13 C NMR (101MHz, CDCl3) 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 ( 1 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 52%; main product:by product (selectivity ratio) = 5:95; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, with a heating rate of 15℃ / min);

[0151] Compound 21

[0152] 1-(4-((4-trifluoromethylphenyl)methyl)phenyl)ethyl-1-one

[0153] Compound II is 1-((4-trifluoromethylphenyl)methyl)-4-ethylbenzene, and the catalyst is catalyst I;

[0154] Yellow oily liquid (9.6 mg, 20%). 1 H NMR (400MHz, CDCl3) δ7.93–7.81(m,2H),7.78–7.73(m,4H),7.38–7.29(m,2H),2.75(q,J=7.6Hz,2H),1.29(t,J=7.6Hz,3H). 13 C NMR (101MHz, CDCl3) 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 (377MHz, CDCl3) δ -63.3. Total yield ( 1 ¹H NMR (400MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) = 75%; main product:by product (selectivity ratio) = 63:37; GC-FID determination (temperature: 60℃ for 2 min to 280℃ for 2 min, with a heating rate of 15℃ / min);

[0155] Example 3: Comparison of Catalytic Conditions

[0156] (1) Using compound I as a substrate, the present invention tested the oxidation effect of different catalysts according to the reaction conditions 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 regioselective for the same substrate. At the same time, the catalyst solves the problem of over-oxidation that often occurs in NHPI catalysts.

[0157] Table 3 Note: "Combined yield" refers to the percentage of the total mass of the main product and byproduct in the reaction solution (derived from coarse NMR spectrum); "over-oxidation" refers to the percentage of the total mass of the dicarbonyl compound in the reaction solution where both benzylic sites are oxidized (derived from coarse NMR spectrum); the regioselectivity of the reaction is determined by GC-FID detection before column chromatography separation of the reaction solution.

[0158] (2) Solvent comparison

[0159] Following the procedure in Example 1, the anode electrode was replaced with a mesh glassy carbon electrode (RVC), the current was 1.0 mA, and 8 mL of each of the solvents shown in the table below were used. The reaction results are shown in Table 4.

[0160] Table 4

Claims

1. A method for preparing compound I, characterized in that, It includes the following steps: in a solvent, in the presence of a catalyst and a basic reagent, compound II undergoes 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 haloalkane solvent, a ketone solvent, or a nitrile solvent.

2. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The solvent is 1,2-dichloroethane, acetone or acetonitrile; preferably 1,2-dichloroethane; (2) The basic reagent is pyridine substituted with one or more C1-C4 alkyl groups; the C1-C4 alkyl group is preferably methyl, for example, the basic reagent is 2,6-dimethylpyridine; (3) The electrolytic oxidation reaction is carried out under oxygen conditions, for example, in an oxygen atmosphere of 1 atm; (4) The oxidation reaction is carried out in the presence of an electrolyte; (5) The reaction apparatus for the electrolytic oxidation reaction includes an anode electrode, a cathode electrode and an electrolyte; the anode electrode is preferably a carbon felt electrode, a carbon plate, a platinum electrode or a mesh glassy carbon electrode; the cathode electrode is preferably 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 to 1.5 mA; preferably 0.5 mA; (7) The voltage of the electrolytic oxidation reaction does not exceed 2.5V, for example, 2.0 to 2.5V; preferably 2.3V or 2.5V; (8) The reaction temperature of the electrolytic oxidation reaction is 21 to 50°C, for example, 30°C; (9) The electrolytic oxidation reaction further includes the following steps: after the reaction is completed, an ester solvent is added, washed, concentrated, and purified by silica gel column chromatography to obtain compound I.

3. The preparation method according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The electrolyte is a buffer salt or an organic ammonium salt, such as [PyH]BF4, [2,6-lutH]BF4, [2,4,6-ColH]BF4, n Bu4ClO4、 n Bu4NCl or n Bu4NBF4, preferably [2,6-lutH]BF4; (2) The molar volume ratio of the electrolyte to the solvent is 0.05-0.4 mol / L, preferably 0.1 mol / L; (3) The anode electrode is immersed in the solution for at least 1 cm; (4) The concentration of compound II in the solvent is 0.01-0.05 mmol / mL, for example, 0.025 mmol / mL; (5) The molar ratio of compound II to the catalyst is 1:(0.1-0.5), preferably 1:0.2; (6) The molar ratio of compound II to the electrolyte is 1:(2-5), preferably 1:4; (7) The molar ratio of compound II to the alkaline reagent is 1:(0.5-5), preferably 1:0.5; (8) The anode electrode is a carbon felt electrode; (9) The cathode electrode is a platinum sheet electrode; (10) The electrolytic oxidation reaction includes 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 for the electrolytic oxidation reaction are compound II, the catalyst, oxygen, 2,6-dimethylpyridine tetrafluoroboric acid, 2,6-dimethylpyridine, and dichloroethane; wherein, the catalyst is 4. The preparation method according to any one of claims 1 to 3, characterized in that, The C1-C 10 Alkyl groups are straight-chain or branched C1-C 10 Alkyl groups; such as straight-chain or branched C1-C6 alkyl groups; preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, etc.

5. The preparation method according to any one of claims 1 to 3, characterized in that, The C4-C 12 The cycloalkyl group is C4-C 12 Monocyclic, bicyclic, or bridged alkyl groups; for example 6. The preparation method according to any one of claims 1 to 3, characterized in that, The compound I is 7. The preparation method according to any one of claims 1 to 3, characterized in that, The compound II is 8. The preparation method according to any one of claims 1 to 3, characterized in that, The catalyst is 9. A method for preparing compound III, characterized in that, It includes the following steps: in a solvent, in the presence of a catalyst and a basic reagent, compound IV undergoes an electrolytic oxidation reaction to generate compound III; Wherein, R2 is cyclopropyl, phenyl, or is replaced by one or more R 2-1 Substituted phenyl; R 2-1 It is an unsubstituted or substituted C1-C4 alkyl or an unsubstituted or substituted C1-C4 alkoxy group; The solvent, catalyst, basic reagent, and electrolytic oxidation reaction are as described in any one of claims 1 to 8.

10. The preparation method according to claim 9, characterized in that, It satisfies one or more of the following conditions: (1) The halogen is independently F, Cl, Br or I; (2) Compound III is any one of the following: (3) Compound IV is any one of the following:

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