A method of oxidation of a diketone-mediated benzyl c-h compound, halide, alkene, alkyne, or alcohol

Abstract

An oxidation strategy of benzyl C-H compounds, halides, alkenes, alkynes or alcohols mediated by butanedione, which can efficiently prepare alcohol, aldehyde, ketone or carboxylic acid compounds by using 1o, 2oor 3obenzyl C-H compounds, halides, alkenes, alkynes or alcohols as raw materials, adding butanedione, acid and solvent, and then irradiating under oxygen condition by visible light. The method provides an oxidation method for many natural products, drugs and materials, which does not need traditional oxidants, does not use transition metal catalysts, uses cheap butanedione as photosensitizer, uses water as solvent, and efficiently oxidizes 1o, 2oor 3obenzyl C-H compounds, halides, alkenes, alkynes or alcohols to prepare alcohol, aldehyde, ketone and carboxylic acid compounds under the induction of visible light. The whole production process is green, low-cost, wide-substrate applicability, high-yield, simple operation, no explosion risk, and has very significant advantages compared with the previous production process.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for oxidizing a benzyl C-H compound, a halide, an alkene, an alkyne or an alcohol into a corresponding ketone, alcohol, aldehyde or carboxylic acid, belonging to the field of chemical synthesis. BACKGROUND

[0002] Oxidation of organic compounds is one of the most useful transformations in organic synthesis, which is widely used in the production of pharmaceutical and chemical industries for the synthesis of various key chemicals and intermediates. However, the oxidation methods disclosed in the prior art mostly use stoichiometric traditional oxidants such as potassium permanganate, osmium tetroxide, peroxide, high-valence iodide, etc. (Chem. Pharm. Bull., 2006, 54, 1620-1621; J. Am. Chem. Soc., 2001, 123, 3183-3185; Chem. Asian J., 2021, 16, 3114-3117; Org. Prep. Proced. Int., 2020, 52, 120-126.), which may have problems such as inconvenience of storage, high risk of operation safety, high cost, and environmental pollution. Oxygen is a green and environmentally friendly, low-cost, safe and easy-to-obtain oxidant, but most of the existing methods using oxygen as an oxidant use organic solvents as reaction media, and mostly use expensive catalysts, complex ligands, special enzyme systems or easily residual transition metals as catalysts for the reaction (Green Chem., 2020, 22, 4357-4363; ACS Sustainable Chem. Eng., 2022, 10, 9591-9599; Green Chem., 2022, 24, 124-129; Org. Lett., 2022, 24, 3920-3925; ChemSusChem, 2021, 14, 2689-2693; Tetrahedron Lett., 2016, 57, 3294-3297; Angew. Chem., 2020, 132, 417-425; J. Org. Chem., 2020, 86, 1164-1171; ChemSusChem, 2022, 15, e202102326), thus inevitably having problems such as high cost of catalysts or ligands, environmental pollution of transition metals or organic solvents, and metal residue. Therefore, it is urgent to develop a simple, efficient, green, inexpensive oxidation system using oxygen as an oxidant and water as a reaction medium. SUMMARY

[0003] The present application aims to solve the technical problem that the existing synthesis method needs to add a stoichiometric amount of oxidant, use expensive transition metals or ligands or catalysts, resulting in high reaction cost and environmental pollution in the oxidation of benzyl C-H compounds, halides, alkenes, alkynes or alcohols.

[0004] To solve the above technical problems, the present application adopts the following technical solutions:

[0005] A strategy for effectively oxidizing benzyl C-H compounds, halides, alkenes, alkynes or alcohols to alcohols, aldehydes, ketones or carboxylic acids under the irradiation of purple light, using butanedione as a photosensitizer, water as a solvent, and O2 as an oxidant. The strategy includes the following steps: adding butanedione and a solvent in a quartz tube, and irradiating with visible light under oxygen conditions, wherein 2° benzyl C-H compounds (A), 3° benzyl C-H compounds (C), and 1° benzyl C-H compounds (E) are oxidized to aryl ketones (B), aryl alcohols (D), and aryl carboxylic acids (F), respectively; 2° benzyl halide compounds (G) and 1° benzyl halide compounds (H) are oxidized to aryl ketones (B) and aryl carboxylic acids (F), respectively; 1,1-disubstituted alkenes (I) are oxidized to aryl ketones (B); monosubstituted alkenes (J) or alkynes (K) are oxidized to aryl carboxylic acids (F); 1° benzyl alcohol (L) and 2° benzyl alcohol (N) are oxidized to aryl aldehydes (M) and aryl ketones (B), respectively; adding butanedione, acetic acid and a solvent in a quartz tube, and irradiating with visible light under oxygen conditions, 2° aliphatic alcohol (O) is oxidized to aliphatic ketone (P). The chemical formula is as follows:

[0006]

[0007] In the above formulas:

[0008] The Ar is a phenyl substituted with bromine, fluorine, chlorine, methoxy, acetyl, phenyl, hydrogen, tert-butyl, trifluoromethoxy, etc.

[0009] The R is a halogen-substituted phenyl, methyl, ethylene, propylene, cyclopropyl, phenyl, bromomethylene, hydroxyethyl, methoxyacyl, ethynyl, hydroxymethyl, benzyl, pentyl, hexyl.

[0010] The amount of butanedione used is 1-10 equivalents.

[0011] The amount of acetic acid used is 0-16 equivalents.

[0012] The solvent is water, N,N-dimethylformamide, chloroform, acetonitrile, acetone, dimethyl sulfoxide, methanol.

[0013] The light is purple light (410-430 nm).

[0014] The working principle of the present application: the applicant found that a kind of butanedione as photosensitizer can excite oxygen to convert into singlet oxygen or peroxide radical after absorbing violet light, and then oxidize benzyl C-H compound, halide, alkene, alkyne or alcohol into corresponding ketone, alcohol, aldehyde or carboxylic acid.

[0015] The method uses cheap and readily available butanedione as photosensitizer under oxygen condition, without adding additional oxidant, and has the advantages of wide substrate applicability, simple operation, high reaction efficiency, green environmental protection, less pollution and the like.

[0016] The beneficial effects of the above technical solution are:

[0017] 1. Compared with the prior art, the present application is suitable for a method for catalytically oxidizing 1°, 2° or 3° benzyl C-H compound, halide, alkene, alkyne or alcohol using butanedione, and the method has wide applicability.

[0018] 2. The method of the present application does not need traditional oxidant, uses stable and cheap butanedione as photosensitizer, does not need transition metal catalyst, and does not need expensive photocatalyst, so the cost is low.

[0019] 3. The present application uses water as solvent to obtain the best yield, uses visible light excitation, and has simple operation, high yield, green and environmental protection compared with the prior art, and has significant economic efficiency. DETAILED DESCRIPTION

[0020] The present application will be further described in combination with specific embodiments. It should be understood that these embodiments are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, and the reaction temperature is room temperature unless otherwise specified. Unless otherwise specified, percentages and parts are calculated by weight. The following examples use conventional post-treatment methods for purification.

[0021] Reaction equation:

[0022] Example 1:

[0023]

[0024] Into a 10 mL quartz reaction tube was added 1-bromo-4-ethylbenzene (A-1, 0.15 mmol), butanedione, water (0.6 mL) successively, and then bubbled with oxygen for 15 minutes. The reaction tube was sealed and stirred at room temperature for 24 hours under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white solid of p-bromoacetophenone (B-1) was obtained by column chromatography using petroleum ether / ethyl acetate (70:1) as the eluent. 1 H NMR (400 MHz, CDC13) δ 7.79 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 2.56 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 197.1, 135.8, 131.9, 129.9, 128.4, 26.6.

[0025] In this example, different amounts of butanedione and solvents were used, and the results are shown in the following table.

[0026]

[0027]

[0028] Example Two:

[0029]

[0030] Into a 10 mL quartz reaction tube was added 1-bromo-4-ethylbenzene (A-1, 0.15 mmol), butanedione, water (0.6 mL) successively, and then bubbled with oxygen for 15 minutes. The reaction tube was sealed and stirred at room temperature for 24 hours under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white solid of p-bromoacetophenone (B-1) was obtained by column chromatography using petroleum ether / ethyl acetate (70:1) as the eluent.

[0031] In this example, different 2° benzyl C-H compounds were used, and the results are shown in the following table.

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] Example Three:

[0038]

[0039] Into a 10 mL quartz reaction tube was added 3° benzyl C-H compound (C, 0.15 mmol), butanedione (0.45 mmol), water (0.6 mL), and then bubbled with oxygen for 15 min. The reaction tube was sealed and stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate (20: 1) as the eluent to give aryl alcohol (D). 1 H NMR (400 MHz, CDC13) δ 7.97 (d, J = 6.9 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 4.04 (t, J = 5.3 Hz, 2H), 3.24 (t, J = 5.3 Hz, 2H), 2.40 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 200.7, 136.7, 133.7, 128.8, 128.2, 58.2, 40.5.

[0040] Example Four:

[0041]

[0042] Into a 10 mL quartz reaction tube was added 3° benzyl C-H compound (C, 0.15 mmol), butanedione (0.45 mmol), water (0.6 mL), and then bubbled with oxygen for 15 min. The reaction tube was sealed and stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether / ethyl acetate (20: 1) as the eluent to give aryl alcohol (D).

[0043] This example used different 3° benzyl C-H compounds, and the results are listed in the table below.

[0044]

[0045]

[0046] Example Five:

[0047]

[0048] Into a 10 mL quartz reaction tube was added 1°benzyl C-H compound (E, 0.15 mmol), dimedone (0.45 mmol), water (0.6 mL), and then bubbled with oxygen for 15 min. The reaction tube was sealed and stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin layer chromatography with petroleum ether / ethyl acetate (10:1) as the eluent to give carboxylic acid F.

[0049] In this example, different 1°benzyl C-H compounds were used, and the results are listed in the following table.

[0050]

[0051]

[0052] Example Six:

[0053]

[0054] Into a 10 mL quartz reaction tube was added 2°benzyl halogenated compound (G, 0.15 mmol), dimedone (0.45 mmol), water (0.6 mL), and then bubbled with oxygen for 15 min. The reaction tube was sealed and stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether as the eluent to give aryl ketone (B).

[0055] In this example, different 2°benzyl halogenated compounds were used, and the results are listed in the following table.

[0056]

[0057] Example Seven:

[0058]

[0059] Into a 10 mL quartz reaction tube, 1° benzyl halide compound (H, 0.15 mmol), butanedione (0.45 mmol), water (0.6 mL) were added successively, and then the reaction tube was sealed and bubbled with oxygen for 15 min. The reaction was stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) for three times. The combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The aryl carboxylic acid (F) was obtained by column chromatography using petroleum ether / ethyl acetate (10:1) as eluent.

[0060] In this example, different 1° benzyl halide compounds were used, and the results are listed below.

[0061]

[0062] Example Eight:

[0063]

[0064] Into a 10 mL quartz reaction tube, 1,1-disubstituted alkene (I, 0.15 mmol), butanedione (0.45 mmol), water (0.6 mL) were added successively, and then the reaction tube was sealed and bubbled with oxygen for 15 min. The reaction was stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) for three times. The combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The aryl ketone (B) was obtained by column chromatography using petroleum ether / ethyl acetate (50:1) as eluent.

[0065] In this example, different 1,1-disubstituted alkene compounds were used, and the results are listed below.

[0066]

[0067] Example Nine:

[0068]

[0069] Into a 10 mL quartz reaction tube, add monosubstituted alkene (J, 0.15 mmol) or alkyne (K, 0.15 mmol), butanedione (0.45 mmol), water (0.6 mL), then bubble with oxygen for 15 min, seal the reaction tube, and stir at room temperature under irradiation of a purple LED lamp (410-430 nm, 20 W) for 36 h. Extract the reaction solution with ethyl acetate (3 mL*3) three times, wash the combined organic phase with saturated brine (2 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by thin layer chromatography using petroleum ether / ethyl acetate (10:1) as the eluent to obtain aryl carboxylic acid (F).

[0070] This example uses different monosubstituted alkenes or alkynes, and the results are listed below.

[0071]

[0072] Example Ten:

[0073] Into a 10 mL quartz reaction tube, add diphenylacetylene (K-5, 0.15 mmol), butanedione (0.45 mmol), acetonitrile (0.4 mL), water (0.2 mL), then bubble with oxygen for 15 min, seal the reaction tube, and stir at room temperature under irradiation of a purple LED lamp (410-430 nm, 20 W) for 36 h. Extract the reaction solution with ethyl acetate (3 mL*3) three times, wash the combined organic phase with saturated brine (2 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by column chromatography using petroleum ether / ethyl acetate (20:1) as the eluent to obtain 4.4 mg of white solid benzoic acid (F-8) with a yield of 24%, and 15.8 mg of white solid benzoin (F-8') with a yield of 49%. 1 H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 6H), 7.27-7.23 (m, 4H), 4.83 (s, 2H), 2.00 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ 139.8, 128.4, 128.3, 127.2, 78.2.

[0074] Example Eleven:

[0075]

[0076] Into a 10 mL quartz reaction tube was added p-nitrobenzyl alcohol (L-1, 0.15 mmol), dimedone, solvent (0.6 mL) successively, and then bubbled with oxygen for 15 min. The reaction tube was sealed and stirred at room temperature for 24 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The pale yellow needle-like solid p-nitrobenzaldehyde (M-1) was obtained by column chromatography using petroleum ether / ethyl acetate (40:1) as the eluent. 1 H NMR (400 MHz, CDC13) δ 10.16 (s, 1H), 8.40 (d, J = 8.7 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, CDC13) δ 190.5, 151.2, 140.1, 130.6, 124.4.

[0077] The results obtained in this example with different amounts of dimedone and different solvents are shown in the following table.

[0078]

[0079]

[0080] Example Twelve:

[0081]

[0082] Into a 10 mL quartz reaction tube was added 1° benzyl alcohol (L, 0.15 mmol), dimedone (0.6 mmol), water (0.6 mL) successively, and then bubbled with oxygen for 15 min. The reaction tube was sealed and stirred at room temperature for 36 h under irradiation of a purple LED lamp (410-430 nm, 20 W). The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The aryl aldehyde (M) was obtained by column chromatography using petroleum ether / ethyl acetate (40:1) as the eluent.

[0083] The results obtained in this example with different 1° benzyl alcohols are shown in the following table.

[0084]

[0085]

[0086]

[0087]

[0088] Example XIII:

[0089]

[0090] Into a 10 mL quartz reaction tube, 2° benzyl alcohol (N, 0.15 mmol), butanedione (0.6 mmol), water (0.6 mL) were added in turn, and then bubbled with oxygen for 15 minutes. The reaction tube was sealed and stirred at room temperature under the irradiation of a purple LED lamp (410-430 nm, 20 W) for 12 hours. Then, ethyl acetate (3 mL*3) was added, and the organic phase was washed with saturated brine (2 mL*3) three times. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography with petroleum ether / ethyl acetate (50:1) as the eluent to obtain the aryl ketone (B).

[0091] The results obtained from different 2° benzyl alcohols in this example are listed below.

[0092]

[0093] The characterization data of product B are as follows.

[0094]

[0095]

[0096]

[0097] Example XIV:

[0098]

[0099] Into a 10 mL quartz reaction tube, cyclohexanol (O-1, 0.15 mmol), butanedione, acetic acid, water (0.6 mL) were added in turn, and then bubbled with oxygen for 15 minutes. The reaction tube was sealed and stirred at room temperature under the irradiation of a purple LED lamp (410-430 nm, 20 W) for 12 hours. The reaction solution was extracted with ethyl acetate (3 mL*3) three times, and the combined organic phase was washed with saturated brine (2 mL) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure, and the yield of cyclohexanone (P-1) was determined by GC-MS. 1 H NMR (400 MHz, CDCl3) δ 2.32 (t, J = 6.7 Hz, 4H), 1.89-1.80 (m, 4H), 1.75-1.66 (m, 2H). 13 CNMR (100 MHz, CDCl3) δ 212.4, 42.1, 27.1, 25.1.

[0100] The present example uses different equivalents of butanedione, acetic acid, and the results obtained are listed in the following table.

[0101]

[0102]

[0103] Example XV:

[0104]

[0105] Into a 10 mL quartz reaction tube, fatty alcohol (O, 0.15 mmol), butanedione (1.2 mmol), acetic acid (0.75 mmol), water (0.6 mL) were added in turn, and then oxygen was bubbled for 15 minutes with a balloon. The reaction tube was sealed and stirred at room temperature under the irradiation of a purple LED lamp (410-430 nm, 20 W) for 24 hours. The reaction solution was extracted three times with ethyl acetate (3 mL*3), and the combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The fatty ketone (P) was obtained by column chromatography using petroleum ether / ethyl acetate (2:1) as the eluent.

[0106] The present example uses different fatty alcohols and the results obtained are listed in the following table.

[0107]

[0108]

[0109]

[0110]

[0111] All the documents mentioned in the present application are incorporated herein by reference. In addition, it should be understood that various modifications and changes can be made to the present application by those skilled in the art upon reading the above teachings of the present application, and such equivalent forms are also intended to fall within the scope of the appended claims.

[0112] It should be understood that all the technical features described above and the technical features described in detail below (such as the examples) can be combined with each other to form new or preferred technical solutions within the scope of the present application. Due to the limited space, they are not listed one by one here.

Claims

1. A method of oxidation of a benzyl C-H compound, halide, alkene, alkyne or alcohol mediated by butanedione, characterized in that: It comprises the following steps: In the quartz tube, add diketone and solvent, irradiate with visible light under oxygen condition, wherein 2 o benzyl C-H compound (A), 3 o benzyl C-H compound (C), 1 o benzyl C-H compound (E) is oxidized to aryl ketone (B), aryl alcohol (D), aryl carboxylic acid (F) respectively; 2 o benzyl halogenated compound (G) is oxidized to aryl ketone (B); 1 o benzyl halogenated compound (H) is oxidized to aryl carboxylic acid (F); 1,1-disubstituted alkene (I) is oxidized to aryl ketone (B); monosubstituted alkene (J) or alkyne (K) is oxidized to aryl carboxylic acid (F); 1 o benzyl alcohol (L), 2 o benzyl alcohol (N) is oxidized to aryl aldehyde (M), aryl ketone (B) respectively; in the quartz tube, add diketone, acetic acid and solvent, irradiate with visible light under oxygen condition, 2 o fatty alcohol (O) is oxidized to fatty ketone (P); the chemical formula is as follows: In the above formulae: The Ar is bromo, fluoro, chloro, methoxy, acetyl, phenyl, hydrogen, t-butyl, trifluoromethoxy substituted phenyl; The R is halogen substituted phenyl, methyl, ethyl, propyl, cyclopropyl, phenyl, bromomethyl, hydroxyethyl, methoxyacetyl, ethynyl, hydroxymethyl, benzyl, pentyl, hexyl; The R' is methyl, ethyl, propyl, benzyl, pentyl, hexyl; The X is X is Cl Br; The n is 0 or 1; The amount of butanedione is 1-10 equivalents; The amount of acetic acid is 0-16 equivalents; The solvent is water, N,N-dimethylformamide, chloroform, acetonitrile, acetone, dimethyl sulfoxide, methanol; The light is violet light with a wavelength of 410-430 nm.

2. The oxidation method for benzyl CH compounds, halogenated compounds, alkenes, alkynes, or alcohols according to claim 1, characterized in that: The butanedione is a photosensitizer, and the amount is 1-10 equivalents.

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