CN119082750B

CN119082750B - Electrochemical oxidation method for selective benzyl carbon-hydrogen bond

Info

Publication number: CN119082750B
Application number: CN202411208227.5A
Authority: CN
Inventors: 梅天胜; 奚亦凡
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2024-08-30
Filing date: 2024-08-30
Publication date: 2025-10-17
Anticipated expiration: 2044-08-30
Also published as: WO2026046359A1; CN119082750A

Abstract

The invention discloses an electrochemical oxidation method for selective benzyl carbon-hydrogen bond. The invention provides a preparation method of a compound I, which comprises the following steps of generating the compound I by electrolytic oxidation reaction of a compound II in a solvent in the presence of a catalyst and an alkaline reagent. The preparation method provided by the invention combines the N-hydroxy maleimide analogue serving as a large steric hindrance hydrogen atom transfer reagent with organic synthesis for the first time, and obviously improves the regioselectivity of the reaction.

Description

Electrochemical oxidation method for selective benzyl carbon-hydrogen bond

Technical Field

The invention relates to an electrochemical oxidation method for selective benzyl carbon-hydrogen bond.

Background

The electrochemical oxidation reaction has the advantages of mild condition, less pollution and convenient operation. Unlike traditional thermochemical reactions, electrochemical oxidation reactions often require the formation of free radicals by an alkaline-promoted PCET process at the electrode surface, which in turn undergo a hydrogen atom transfer reaction to form intermediates such as benzyl radicals (10.1038/nature 17431; 10.1248/cpb.35.1372). After free radical formation, the product is obtained by oxygen capture.

Regioselectivity is not well-known as a long standing challenge in electrochemical oxidation reactions. In the traditional benzyl electrochemical oxidation reaction, N-hydroxyphthalamide (NHPI) is difficult to distinguish between benzyl hydrocarbon bonds with similar electrical properties and different steric hindrance, and the activity of the N-hydroxyphthalamide is too high, so that excessive oxidation of a substrate is easy to occur, and the application of the N-hydroxyphthalamide (NHPI) in reactions requiring high selectivity is limited.

The invention combines the N-hydroxy maleamide hydroxylamine (NHMI) analogue which is a large steric hindrance hydrogen atom transfer reagent with organic synthesis for the first time. Under electrochemical conditions, the reaction selectivity is regulated and controlled through the catalyst structure, and compared with the catalysis effect of NHPI and analogues thereof, the regioselectivity of the reaction is remarkably improved. The innovative method effectively solves the problem of poor regioselectivity in the field of electrochemical oxidation, and provides a new solution for high-selectivity reaction.

Disclosure of Invention

The invention solves the technical problem of providing a method capable of oxidizing benzyl carbon-hydrogen bonds with high selectivity under electrochemical conditions aiming at the defects of the prior art. The invention provides an electrochemical oxidation method for selective benzyl carbon-hydrogen bond. The method provided by the invention has the effect of realizing high regioselectivity in the field of electrochemical oxidation.

The invention solves the technical problems through the following technical proposal.

The invention provides a preparation method of a compound I, which comprises the following steps that in a solvent, in the presence of a catalyst and an alkaline reagent, a compound II is subjected to electrolytic oxidation reaction to generate the compound I;

;

Wherein R is C ₁-C₁₀ alkyl or ;

N is 0,1, 2 or 3;R ₁ is C ₄-C₁₂ cycloalkyl;

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

the solvent is halogenated hydrocarbon solvent, ketone solvent or nitrile solvent.

In some embodiments of the invention, the solvent may be a halogenated hydrocarbon solvent, a ketone solvent, or a nitrile solvent, such as 1, 2-dichloroethane, acetone, or acetonitrile, preferably 1, 2-dichloroethane.

In some embodiments of the invention, the basic agent is pyridine substituted with one or more C ₁-C₄ alkyl groups, the C ₁-C₄ alkyl group is preferably methyl, and the basic agent is preferably 2, 6-lutidine.

In some embodiments of the invention, the electrolytic oxidation reaction is carried out under oxygen conditions, for example, in a 1atm oxygen atmosphere.

In some embodiments of the invention, the oxidation reaction is performed 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、ⁿBu₄ClO₄、ⁿBu₄NCl or ⁿBu₄NBF₄, preferably [2,6-lutH ] BF ₄.

In some embodiments of the invention, the reaction device for the electrolytic oxidation reaction comprises an anode electrode, which may be a carbon felt electrode, a carbon plate, a platinum electrode or a reticulated vitreous carbon electrode (RVC), preferably a carbon felt electrode, and an electrolyte, preferably a platinum sheet electrode, a carbon felt electrode, a carbon plate or a reticulated vitreous carbon electrode (RVC), preferably a platinum sheet electrode.

In some embodiments of the invention, the electrolytic oxidation reaction may have a molar volume ratio of the electrolyte to the solvent of 0.05 to 0.4mol/L, preferably 0.1 mol/L.

In some embodiments of the present invention, the reaction current of the electrolytic oxidation reaction is 0.5 to 1.5ma, preferably 0.5 mA.

In some embodiments of the invention, the voltage of the electrolytic oxidation reaction is conventional in the art and can be controlled by the reaction current, typically not exceeding 2.5V, for example, 2.0-2.5V, preferably 2.3V or 2.5V.

In some embodiments of the present invention, the reaction temperature of the electrolytic oxidation reaction may be 21 to 50 ℃, for example 30 ℃.

In some embodiments of the invention, the progress of the electrolytic oxidation reaction is detected using conventional monitoring methods of such reactions in the art, such as TLC and the like. Preferably with complete conversion of compound II or no regeneration of compound I to the reaction endpoint. The time of the electrolytic oxidation reaction can be 24-36 h, and is preferably 30h.

In some embodiments of the invention, the anodic electrode is immersed in the solution at least 1cm in the electrolytic oxidation reaction.

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

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

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

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

In some embodiments of the invention, the electrolytic oxidation reaction comprises the step of performing the electrolytic oxidation reaction after the compound II, the catalyst, the electrolyte and the alkaline agent are mixed and dissolved in the solvent in the presence of oxygen.

In some embodiments of the present invention, the electrolytic oxidation reaction further comprises the steps of adding an ester solvent (e.g., ethyl acetate), washing (e.g., with water), concentrating, and purifying by silica gel column chromatography, which may be eluted using procedures and mobile phase ratios conventional in the art, e.g., ethyl acetate/petroleum ether=2:98.

In some embodiments of the invention, the C ₁-C₁₀ alkyl is a linear or branched C ₁-C₁₀ alkyl, such as a linear or branched C ₁-C₈ alkyl (e.g., linear or branched C ₄-C₈ alkyl), preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,、、、、、、Or (b)。

In some embodiments of the invention, the C ₄-C₁₂ cycloalkyl is C ₄-C₁₂ monocyclic, bicyclic or bridged cycloalkyl, e.g、、、Or (b)。

In some embodiments of the invention, the compound I is:、、、、、、、、、、、、、、、 Or (b) 。

In some embodiments of the invention, the compound II is:、、、、、、、、、、、、、、、 Or (b) 。

In some embodiments of the invention, the catalyst is、、Or (b)。

In some embodiments of the invention, the starting materials for the electrolytic oxidation reaction are the compound II, the catalyst, oxygen, 2, 6-dimethylpyridine tetrafluoroboric acid, 2, 6-dimethylpyridine and dichloroethane, wherein the catalyst is。

The invention also provides a preparation method of the compound III, which comprises the following steps that in a solvent, in the presence of a catalyst and an alkaline reagent, the compound IV generates the compound III through electrolytic oxidation reaction;

Wherein R ₂ is cyclopropyl, phenyl, or phenyl substituted with one or more R _2-1, R _2-1 is C ₁-C₄ alkyl optionally substituted with one or more halo, or C ₁-C₄ alkoxy optionally substituted with one or more halo;

the solvent, catalyst, alkaline reagent and electrolytic oxidation reaction are as described above.

In some embodiments of the invention, the halogen is independently F, cl, br or I.

In some embodiments of the invention, the compound III is any one of the following:、、 Or (b) 。

In some embodiments of the invention, the compound IV is any one of the following:、、 Or (b) 。

On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that the N-hydroxyl maleyl hydroxylamine (NHMI) derivative is combined with organic synthesis for the first time, the regioselectivity of the reaction is improved, and the peroxidation phenomenon is reduced.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

1. And (3) synthesizing a catalyst:

n-hydroxymaleimide synthesis can be referenced (T.Kato, K. Maruoka, ANGEWANDTE CHEMIE International Edition 2020, 59, 14261-14264);

The synthetic route of the catalyst I is as follows:

。

2. Electrochemical device construction

A 25ml three-necked flask was taken, a hole was punched in the rubber stopper to pass through the electrode and ensure airtightness, the anode was a carbon felt electrode (10 x 3 x 25 mm), the cathode was a platinum sheet electrode (10 x 10 mm), and then a substrate (0.2 mmol, 1 equiv.), an electrolyte (2, 6-dimethylpyridine tetrafluoroboric acid, 0.1M, 0.8 mmol), and a large steric hindrance catalyst (0.04 mmol, 0.2 equiv) were added to the flask. After the addition, a three-way piston was added to the three-necked flask and the oxygen was exchanged, followed by the addition of 2, 6-lutidine (0.5 equiv, 0.1 mmol, 10.7, mg) and solvent 1, 2-dichloroethane (8 mL). After the addition, the reaction system was placed in a 30 ℃ oil bath and stirred at 800 rpm ℃ for 15: 15 min until all solid material was dissolved.

3. Electrolytic parameters:

The cathode and anode were connected to a dc power supply and the reaction current was set to 0.5 mA and the maximum reaction voltage was 2.5V. The anode position was fine-tuned to be at least 1 cm immersed in the solution with an initial voltage of around 2.3V and electrolysis of 30 h.

4. And (3) reaction treatment:

Dilute brine and a large amount of ethyl acetate are added into the system for extraction, the organic phase obtained by extraction is dried, concentrated and separated by column chromatography (petroleum ether: ethyl acetate=98:2), and the main product is a small steric hindrance oxidation product which is yellow or orange when developed by phenylhydrazine color developing solution.

Regional selectivity determination:

A small amount of the extracted reaction solution was diluted to an appropriate concentration and detected for regioselectivity using a GC-FID detector, as follows:

the chromatographic column is AGILENT HP-5ms Ultra Inert 0-325 (350 ℃) 30m x 250 mu m x 0.25.25 mu m.

260 ℃ Of sample inlet, 20/1 of split sample inlet, 2 mL/min (He) of carrier gas flow,

Pressure 21.844 psi, sample loading 1. Mu.L (using an autosampler).

Column oven 60 ℃ (hold 2 min) was warmed to 280 ℃ (hold 2 min) at 15 ℃ per min.

Detector 280 ℃, H ₂:30 mL/min, air 400: 400 mL/min, tail blow (N ₂): 25: 25 mL/min.

Example 1:

To a three-necked flask, compound II (0.2 mmol,1.0 eq), catalyst (20 mol%,0.04 mmol, 0.2 eq) and 2, 6-dimethylpyridine tetrafluoroboric acid (LutHBF ₄) (0.8 mmol,4.0 eq, 0.1M) were charged under an oxygen atmosphere. Subsequently, 2, 6-lutidine (0.1 mmol,0.5 eq.) and dichloroethane (8 mL) were added to the mixture through a septum at 30 ℃. The mixture was stirred for 15 minutes to dissolve the electrolyte before electrolysis. The mixture was then subjected to electrolysis for 30 hours (0.5 mA, < 2.5V). After the reaction was completed, the mixture was diluted with ethyl acetate and washed with water to remove the electrolyte, followed by concentration under vacuum. The residue was further purified by silica gel column chromatography (eluting with ethyl acetate/petroleum ether=2:98) to give the main product as compound I and the by-product as compound III.

The following compounds were prepared according to the synthesis conditions of example 1:

TABLE 1

。

As can be seen from Table 1, the reaction has good reactivity to substrates with different groups of bit resistance, and compared with NHPI, the NHMI catalyst has more excellent regioselectivity and higher benzylic hydrocarbon selectivity with smaller bit resistance.

The characterization results of the compounds obtained in table 1 are as follows:

Compound 1

1- (4- (Cyclohexylmethyl) phenyl) ethan-1-one (1 a)

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

The overall yield of yellow oil (27.2 mg, 63%). ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.5 Hz, 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). ¹³C 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =77%; main product: by-product (selectivity ratio) =87:13; gc-FID determination (temperature: 180 ℃ 3min to 280 ℃ 2min, temperature increase at 10 ℃ per min); t _R = 5.640 min (by-product), t _R = 5.939 min (main product).

Compound 2

1- (4- (Cyclobutylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (cyclobutylmethyl) -4-ethylbenzene, and the catalyst is catalyst I;

Total yield of colorless oil (17.5 mg, 45%).¹H NMR (400 MHz, CDCl₃) 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). ¹³C NMR (101 MHz, CDCl₃) δ 198.1, 147.3, 135.1, 128.8, 128.6, 43.1, 37.1, 28.3, 26.7, 18.5. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =58% of main product: by-product (selectivity ratio) =62:38 this regioselectivity is determined by ¹H NMR (400 MHz, CDCl₃).

Compound 3

1- (4- (Cyclopentylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (cyclopentylmethyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oil (23.9 mg, 58%).¹H NMR (400 MHz, CDCl₃) 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). ¹³C NMR (101 MHz, CDCl₃) δ 198.1, 148.4, 135.0, 129.1, 128.5, 42.2, 41.8, 32.6, 26.7, 25.0. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =54%; main product: by-product (selectivity ratio) =76:24; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise 15 ℃ per min); t _R = 12.126 min (by-product), t _R = 12.305 min (main product).

Compound 4

1- (4- (Cycloheptylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (cycloheptylmethyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oil (23.5 mg, 51%).¹H NMR (400 MHz, CDCl₃) 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =68%; main product: by-product (selectivity ratio) =89:11; gc-FID determination (temperature: 196 ℃ 2min to 280 ℃ 2min, temperature increase at 10 ℃ per min); t _R = 5.527 min (by-product), t _R = 5.834 min (main product).

Compound 5

Wherein the compound II is 1-cyclohexyl-4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oil (24.3 mg, 60%).¹H 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). ¹³C 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =61%; main product: by-product (selectivity ratio) = >99:1; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 12.244 min (main product).

Compound 6

4-N-pentylacetophenone

Wherein the compound II is 1- (n-amyl) -4-ethylbenzene, and the catalyst is catalyst I;

The total yield of colourless oily liquid (17.6 mg, 49%).¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 8.6 Hz, 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). ¹³C 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =64%; main product: by-product (selectivity ratio) =80:20; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise 15 ℃ per min); t _R = 10.904 min (by-product), t _R =11.000 min (main product).

Compound 7

1- (4- (Isopropylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (isopropyl methyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (27.4mg, 65%).¹H NMR (400 MHz, CDCl₃) 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, 147.7, 135.1, 129.4, 128.4, 45.5, 30.2, 26.7, 22.5. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =86%; main product: by-product (selectivity ratio) =88:12; gc-FID determination (temperature: 112 ℃ 3min to 172 ℃ 3min, heating at 10 ℃ per min), t _R = 7.508 min (by-product), t _R = 7.765 min (main product).

Compound 8

1- (2-Ethylbutylphenyl) ethan-1-one

Wherein the compound II is 1- (2-ethylbutyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (23.1mg, 61%).¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 2.64 – 2.51 (m, 5H), 1.54 (hept, J = 6.0 Hz, 1H), 1.33 – 1.25 (m, 4H), 0.87 (t, J = 7.4 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =71%; main product: by-product (selectivity ratio) =92:8; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 10.929 min (by-product), t _R =11.470 min (main product).

Compound 9

1- (4- (Tert-butylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (tert-butyl methyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (31.6mg, 83%).¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 2.67 (s, 3H), 2.63 (s, 2H), 0.99 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 198.2, 145.8, 135.1, 130.7, 127.9, 50.3, 32.1, 29.5, 26.7. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =97%; main product: by-product (selectivity ratio) = >99:1; gc-FID determination (temperature: 130 ℃ to 190 ℃ for 3min, temperature increase at 10 ℃ per min), t _R = 6.671 min (main product).

Compound 10

1- (4- (Adamantylmethyl) phenyl) ethan-1-one

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

the overall yield of yellow solid (40.7 mg,76%).¹H 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). ¹³C 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, 612cm–1. HRMS (EI-QTOF) calcd. for C19H24O: 268.1822; found: 268.1824. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =95%; main product: by-product (selectivity ratio) = >99:1; gc-FID determination (temperature: 228 ℃ 3min to 280 ℃ 3min, temperature increase at 10 ℃ per min); t _R = 5.686 min (main product). Melting point 74.3-79.2 ℃.

Compound 11

1- (3- (Cyclohexylmethyl) phenyl) ethan-1-one

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

The overall yield of yellow oily liquid (21.0 mg, 48%).¹H NMR (400 MHz, CDCl₃) 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). ¹³C NMR (101 MHz, 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 C15H20O: 216.1509; found: 216.1506. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =68%; main product: by-product (selectivity ratio) =87:13; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 12.599 min (by-product), t _R = 12.788 min (main product).

Compound 12

1- (4- (3-Methyl-n-butyl) phenyl) ethan-1-one

Wherein the compound II is 1- (3-methyl-n-butyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (22.6 mg, 64%).¹H NMR (400 MHz, CDCl₃) 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). ¹³C NMR (101 MHz, CDCl₃) δ 198.0, 149.1, 134.9, 128.6, 128.5, 40.4, 33.9, 27.7, 26.6, 22.5. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =66%; main product: by-product (selectivity ratio) =87:13; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 10.446 min (by-product), t _R = 10.713 min (main product).

Compound 13

1- (4- (3-Ethyl-n-pentyl) phenyl) ethan-1-one

Wherein the compound II is 1- (3-ethyl-n-amyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (22.0 mg, 50%).¹H NMR (400 MHz, CDCl₃) 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =55%; main product: by-product (selectivity ratio) =91:9; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise 15 ℃ per min); t _R = 12.037 min (by-product), t _R = 12.320 min (main product).

Compound 14

1- (4- (3, 3-Dimethyl-n-butyl) phenyl) ethan-1-one

Wherein the compound II is 1- (3, 3-dimethyl-n-butyl) -4-ethylbenzene, and the catalyst is a catalyst I;

The overall yield of yellow oily liquid (22.6 mg, 57%).¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 8.4 Hz, 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). ¹³C NMR (101 MHz, CDCl₃) δ 198.0, 149.7, 135.0, 128.7, 46.1, 31.5, 30.7, 29.4, 26.7. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =73%; main product: by-product (selectivity ratio) =95:5; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise 15 ℃ per min); t _R = 10.730 min (by-product), t _R = 11.224 min (main product).

Compound 15

1- (4- (2-Adamantylethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (2-adamantylethyl) -4-ethylbenzene, and the catalyst is catalyst I;

the overall yield of yellow solid (32.8 mg, 58%).¹H 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). ¹³C 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =67%; main product: by-product (selectivity ratio) =91:9; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 16.381 min (by-product), t _R = 16.926 min (main product).

Compound 16

1- (4- (4-Methyl-n-pentyl) phenyl) ethan-1-one

Wherein the compound II is 1- (4-methyl-n-amyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow solid (19.8mg, 51%).¹H 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). ¹³C 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =69%; main product: by-product (selectivity ratio) =77:23; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 11.388 min (by-product), t _R = 11.488 min (main product).

Compound 17

1- (4, 4-Dimethyl-n-pentyl) phenyl) ethan-1-one

Wherein the compound II is 1- (4, 4-dimethyl-n-amyl) -4-ethylbenzene, and the catalyst is a catalyst I;

The overall yield of yellow solid (21.4mg, 56%).¹H 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). ¹³C NMR (101 MHz, 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =59%; main product: by-product (selectivity ratio) =76:24; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 11.537 min (by-product), t _R = 11.630 min (main product).

Example 2:

TABLE 2

。

As can be seen from table 2, when the present invention is applied to a substrate in which an electron-rich group is partially present, the regioselectivity of the reaction is reversed due to the better stable free radical of the electron-rich group, but the NHMI catalyst still shows a higher tendency for oxidation of the less sterically hindered benzylic hydrocarbon than NHPI.

The characterization results of the compounds obtained in table 2 are as follows:

Compound 18

1- (4- (Cyclopropylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (cyclopropylmethyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (10.7mg, 34%).¹H 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). ¹³C 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =51%; main product: by-product (selectivity ratio) =34:66; regioselectivity is determined by ¹H NMR (400 MHz, CDCl₃).

Compound 19

1- (4- (Phenylmethyl) phenyl) ethan-1-one

Wherein the compound II is 1- (phenylmethyl) -4-ethylbenzene, and the catalyst is catalyst I;

The overall yield of yellow oily liquid (26.9 mg).¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 8.4 Hz, 2H), 7.39 – 7.12 (m, 7H), 4.06 (s, 2H), 2.60 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 198.0, 147.0, 140.2, 135.4, 129.2, 129.1, 128.8, 128.8, 126.5, 42.0, 26.7. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =67%; main product: by-product (selectivity ratio) =44:56; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min); t _R = 12.975 min (by-product), t _R = 12.815 min (main product).

Compound 20

1- (4- ((4-Methoxyphenyl) methyl) phenyl) ethan-1-one

Wherein the compound II is 1- ((4-methoxyphenyl) methyl) -4-ethylbenzene, and the catalyst is catalyst I;

Total yield of colorless oily liquid (20.0 mg, 49%). ¹H NMR (400 MHz, CDCl₃) 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). ¹³C NMR (101 MHz, 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. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =52%; main product: by-product (selectivity ratio) =5:95; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min);

compound 21

1- (4- ((4-Trifluoromethylphenyl) methyl) phenyl) ethan-1-one

Wherein the compound II is 1- ((4-trifluoromethyl phenyl) methyl) -4-ethylbenzene, and the catalyst is a catalyst I;

overall yield of yellow oily liquid (9.6 mg, 20%).¹H NMR (400 MHz, CDCl₃) 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). ¹³C NMR (101 MHz, 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 (377 MHz, CDCl₃) δ -63.3. (¹H NMR (400 MHz, CDCl₃) 14μL CH₂Br₂ as internal standard) =75%; main product: by-product (selectivity ratio) =63:37; gc-FID determination (temperature: 60 ℃ 2min to 280 ℃ 2min, temperature rise at 15 ℃ per min);

Example 3 comparison of catalytic conditions

(1) According to the reaction conditions of the embodiment I, the oxidation effect of different catalysts is tested by taking the compound I as a substrate, and as can be seen from the table 3, compared with the traditional NHPI type catalyst, the newly developed large steric hindrance NHMI type catalyst is more excellent in regioselectivity on the same substrate, and meanwhile, the catalyst solves the problem of excessive oxidation frequently occurring in the NHPI catalyst.

TABLE 3 Table 3

Note that "combined yield" refers to the percentage of total material in the reaction solution (from the crude nuclear magnetic resonance spectrum) of the main product and the by-product, and "over-oxidation" refers to the percentage of total material in the reaction solution (from the crude nuclear magnetic resonance spectrum) of the dicarbonyl compound in which both benzyl positions are oxidized, and the regioselectivity of the reaction is determined by GC-FID detection before the chromatographic separation of the reaction solution.

(2) Solvent comparison

Referring to the operation of example 1, the anode electrode was replaced with a reticulated vitreous carbon electrode (RVC) at a current of 1.0mA, 8mL each of the solvents shown in the following table were used, and the reaction results are shown in Table 4.

TABLE 4 Table 4

。

Claims

1. A preparation method of the compound I is characterized by comprising the following steps of generating the compound I by electrolytic oxidation of the compound II in a solvent in the presence of a catalyst and an alkaline reagent;

Wherein R is C ₁-C₁₀ alkyl or

N is 0,1, 2 or 3;R ₁ is C ₄-C₁₂ cycloalkyl;

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

the solvent is halogenated hydrocarbon solvent, ketone solvent or nitrile solvent;

The basic agent is pyridine substituted with one or more C ₁-C₄ alkyl groups.

2. The method of claim 1, wherein one or more of the following conditions are satisfied:

(1) The solvent is 1, 2-dichloroethane, acetone or acetonitrile;

(2) The C ₁-C₄ alkyl is methyl;

(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 for the electrolytic oxidation reaction comprises an anode electrode, a cathode electrode and electrolyte;

(6) The reaction current of the electrolytic oxidation reaction is 0.5-1.5 mA;

(7) The voltage of the electrolytic oxidation reaction is not more than 2.5V;

(8) The reaction temperature of the electrolytic oxidation reaction is 21-50 ℃;

(9) The electrolytic oxidation reaction also comprises the steps of adding an ester solvent after the reaction is finished, washing, concentrating, and purifying by adopting a silica gel column chromatography to obtain the compound I.

3. The preparation method according to claim 2, characterized in that it satisfies 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 reacted in an oxygen atmosphere of 1 atm;

(4) The anode electrode is a carbon felt electrode, a carbon plate, a platinum electrode or a reticular glassy carbon electrode;

(5) The cathode electrode is a platinum sheet electrode, a carbon felt electrode, a carbon plate or a netlike glassy carbon electrode;

(6) The reaction current of the electrolytic oxidation reaction is 0.5mA;

(7) The voltage of the electrolytic oxidation reaction is 2.0-2.5V;

(8) The reaction temperature of the electrolytic oxidation reaction is 30 ℃.

4. The method of claim 2, wherein the electrolytic oxidation reaction has a voltage of 2.3V or 2.5V.

5. The preparation method according to claim 2, characterized in that it satisfies one or more of the following conditions:

(1) The electrolyte is Buffer salt or organic ammonium salt;

(2) The molar volume ratio of the electrolyte to the solvent is 0.05-0.4mol/L;

(3) The anode electrode is immersed in the solution for at least 1cm;

(4) The concentration of the compound II in the solvent is 0.01-0.05mmol/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 sheet electrode;

(10) The electrolytic oxidation reaction comprises the following reaction steps of carrying out electrolytic oxidation reaction after the compound II, the catalyst, the electrolyte and the alkaline reagent are mixed and dissolved in the solvent in the presence of oxygen;

(11) The raw materials of the electrolytic oxidation reaction are the compound II, the catalyst, oxygen, 2, 6-dimethylpyridine tetrafluoroboric acid, 2, 6-dimethylpyridine and dichloroethane, wherein the catalyst is

6. The preparation method according to claim 2, characterized in that it satisfies one or more of the following conditions:

(1) The electrolyte is [PyH]BF₄、[2,6-lutH]BF₄、[2,4,6-ColH]BF₄、ⁿBu₄ClO₄、ⁿBu₄NCl or ⁿBu₄NBF₄;

(2) The molar volume ratio of the electrolyte to the solvent is 0.1mol/L;

(3) The concentration of the compound II in the solvent is 0.025mmol/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 method of claim 5, wherein the electrolyte is [2,6-lutH ] BF ₄.

8. The method according to any one of claims 1 to 7, wherein the C ₁-C₁₀ alkyl group is a linear or branched C ₁-C₁₀ alkyl group.

9. The method of claim 8, wherein the C ₁-C₁₀ alkyl is a linear or branched C ₁-C₆ alkyl.

10. The process according to claim 8, wherein the C ₁-C₁₀ alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,

11. The method of any one of claims 1-7, wherein the C ₄-C₁₂ cycloalkyl is C ₄-C₁₂ monocyclic, bicyclic or bridged cycloalkyl.

12. The method of claim 11, wherein said C ₄-C₁₂ cycloalkyl is

13. The process according to any one of claims 1 to 7, wherein the compound I is

14. The method according to any one of claims 1 to 7, wherein the compound II is

15. The method according to any one of claims 1 to 7, wherein the catalyst is

16. A preparation method of the compound III is characterized by comprising the following steps of generating the compound III by electrolytic oxidation of the compound IV in a solvent in the presence of a catalyst and an alkaline reagent;

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

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

18. The method of claim 16, which satisfies 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) The compound IV is any one of the following: