Process for the selective oxidation of benzyl and allyl compounds

Abstract

The application discloses a selective oxidation method of benzyl compounds and allyl compounds. The method uses benzyl compounds and allyl compounds as raw materials, halogenated alkane as a catalytic reagent, acetonitrile as a reaction solvent, air as a molecular oxygen source, and performs a reaction under light conditions to selectively oxidize to generate benzyl ketone compounds and allyl compounds. The method has the advantages of high reaction efficiency, mild reaction conditions, convenient operation, economy and greenness, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to a selective oxidation method for benzyl and allyl compounds, which uses photoactivated molecular oxygen of haloalkane to oxidize benzyl and allyl compounds, thereby selectively oxidizing them to benzyl ketones and allyl ketones, and belongs to the field of organic synthesis. Background Technology

[0002] Carbonyl compounds are widely found in various natural and chemical products, among which benzyl ketones and allyl ketones are the most widely used. They have extremely high application value in industrial production, drug molecule synthesis, and as intermediates.

[0003] There are several methods for synthesizing benzyl ketones from benzyl compounds, the most common being the Friedel-Crafts reaction, which involves the reaction of benzene with acetyl chloride, acetic anhydride, or acetic acid under stoichiometric anhydrous aluminum trichloride catalysis. This synthesis method generates large amounts of toxic, difficult-to-treat, and costly organic waste liquid, and also suffers from problems such as large catalyst consumption and difficulty in product separation. In gas-solid phase catalytic reaction systems, the requirements for catalysts and reaction equipment are high, and the reaction temperature is high, consuming large amounts of non-renewable energy. Currently, industrially, metal complexes are used for homogeneous high-temperature oxidation, but the yield is low. The synthesis of allyl ketones often requires highly toxic reagents (based on toxic elements such as chromium and selenium) or expensive catalysts (such as palladium and rhodium), which conflicts with the principles of green chemistry.

[0004] In recent years, metal complexes and metal molecular sieves such as Cr, combined with peroxides such as H2O2 and TBHP, have been used to prepare benzyl ketones and allyl ketones by light irradiation. However, such reactions require the consumption of large amounts of peroxides, which raises concerns about cost and safety. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a selective oxidation method for benzyl and allyl compounds. This method offers advantages such as high reaction efficiency, mild reaction conditions, convenient operation, and economic efficiency, and is suitable for large-scale production.

[0006] The selective oxidation method of benzyl and allyl compounds of the present invention uses benzyl or allyl compounds as raw materials, haloalkanes as catalysts, and air as a source of molecular oxygen, and carries out the reaction under light conditions. After separation and purification, benzyl ketone compounds or allyl ketone compounds are obtained.

[0007] Specifically, benzyl or allyl compounds are dissolved in a solvent in an air atmosphere, a haloalkane is added as an activating agent for molecular oxygen, and the reaction is carried out under light conditions. After the reaction is completed, the benzyl ketone compounds or allyl ketone compounds are obtained by separation and purification.

[0008] The structure of the benzyl compound is shown below:

[0009]

[0010] The structure of the allyl compound is shown below:

[0011]

[0012] R3 and R4 are long-chain alkyl groups with a total of 6-32 carbon atoms.

[0013] The haloalkane is selected from compounds with the following structures:

[0014]

[0015] The amount of the haloalkane added is 5-20 eq, based on the substrate.

[0016] The solvent is selected from acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, toluene, nitromethane, or tetrahydrofuran.

[0017] The reaction temperature is 25-35℃, preferably 30℃, and the reaction time is 3-24h.

[0018] The wavelength of the light is 365nm-455nm.

[0019] The separation and purification process involves adding a saturated sodium bicarbonate aqueous solution to the reaction solution, extracting three times with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and then performing column chromatography. The eluent for column chromatography separation and purification is petroleum ether:ethyl acetate = 20:1 to 1:1, v / v.

[0020] The reaction route of this invention is shown below:

[0021]

[0022]

[0023] The beneficial effects of this invention are reflected in:

[0024] 1. The synthesis method of the present invention is characterized by being green and efficient, having high yield, and having a wide substrate range.

[0025] 2. The synthesis method of the present invention is simple, the synthesis time is short, the reaction can be carried out at room temperature and pressure, it is easy to operate, and the product has good selectivity and high yield.

[0026] 3. The synthesis method of the present invention is applicable to the site-selective oxidation of benzyl and allyl groups in drug molecules.

[0027] 4. The haloalkane used for catalysis in the reaction can be recycled by redistilling, eliminating the residue of heavy metals or the need for post-treatment of toxic reagent waste liquid from previous reactions, thus reducing environmental harm and lowering reaction costs. Detailed Implementation

[0028] To further illustrate the features and advantages of the present invention, the technical solution of the present invention is described below with reference to specific embodiments. However, the following embodiments are only for further illustration of the present invention and are not intended to limit the present invention.

[0029] Example 1:

[0030]

[0031] To a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, 0.2 mmol of ethylbenzene 1a and 1 mmol of dibromoethane were added, followed by 2 mL of anhydrous acetonitrile under air. The reaction was carried out at room temperature for 5 h under illumination at 395 nm. The mixture was then extracted three times with saturated sodium bicarbonate aqueous solution and ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a colorless, transparent liquid 1b (23 mg, 96%). The NMR data for this compound are as follows: 1 H NMR (600MHz, Chloroform-d) δ7.94(d,J=7.9Hz,2H),7.54(t,J=7.3Hz,1H),7.44(t,J=7.7Hz,2H),2.59(s,3H). 13 C NMR(151MHz,Chloroform-d)δ198.11,137.08,133.08,128.54,128.27,126.59.

[0032] Example 2:

[0033]

[0034] Diphenylmethane 2a was used instead of ethylbenzene 1a, and the reaction time was 6 h, otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid 2b (34.6 mg, 95%). The NMR data of this compound are as follows: 1HNMR(600MHz,Chloroform-d)δ7.81(d,J=7.3Hz,2H),7.58(t,J=7.4Hz,1H),7.47(t,J=7.7Hz,2H).

[0035] 13 C NMR(151MHz,Chloroform-d)δ196.71,137.57,132.43,130.05,128.28.

[0036] Example 3:

[0037]

[0038] 4-Nitrophenylethyl bromide 3a was used instead of ethylbenzene 1a, and the reaction time was 24 h, otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give a pale yellow solid 3b (39.7 mg, 82%). The NMR data of this compound are as follows: 1 H NMR (600MHz, Chloroform-d) δ8.34 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 9.0 Hz, 2H), 4.46 (s, 2H). 13 C NMR(151MHz,Chloroform-d)δ190.03,150.83,138.49,130.22,124.18,30.26.

[0039] Example 4:

[0040]

[0041] Phthalic acid 4a was used instead of ethylbenzene 1a, and the reaction time was 24 h, otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid 4b (26.4 mg, 74%). The NMR data of this compound are as follows: 1 HNMR (600MHz, Chloroform-d) δ7.98(dd,J=8.4,1.3Hz,2H),7.57(t,J=7.4Hz,1H),7.47(t,J=7.7Hz,2H),3.31(t,J=6.6Hz,2H),2.81(t,J=6.6Hz,2H). 13 C NMR (151MHz, Chloroform-d) δ197.97,179.04,136.48,133.46,128.77,128.17,33.28,28.18.

[0042] Example 5:

[0043]

[0044] 4-Phenylonitrile 5a was used instead of ethylbenzene 1a, and the reaction time was 12 h, otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a clear oily liquid 5b (28.1 mg, 89%). The NMR data of this compound are as follows: 1 H NMR (600MHz, Chloroform-d) δ7.94(d,J=7.2Hz,2H),7.61(t,J=7.4Hz,1H),7.49(t,J=7.8Hz,2H),3.38-3.36(m,2H),2.76(t,J=7.2Hz,2H). 13 C NMR (151MHz, Chloroform-d) δ195.45,135.67,133.97,128.95,128.09,119.34,34.33,11.87.

[0045] Example 6:

[0046]

[0047] Boc-D-homophenylalanine 6a was used instead of ethylbenzene 1a, and the reaction time was 24 h, otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a clear oily liquid 6b (49.7 mg, 81%). The NMR data of this compound are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.94(d,J=7.3Hz,2H),7.58(t,J=7.4Hz,1H),7.47(t,J=7.8Hz,2H),5.62(d,J=8.5H z,1H),4.69(dt,J=8.3,3.9Hz,2H),3.74(s,3H),3.72(d,J=4.0Hz,1H),3.53(dd,J=18.1,4.0Hz,1H),1.43(s,9H). 13 C NMR (151MHz, Chloroform-d) δ197.78,172.02,155.56,136.01,133.70,128.71,128.13,80.00,52.64,49.53,40.94,28.29.

[0048] Example 7:

[0049]

[0050] To a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, 0.2 mmol of progesterone 7a and 2 mmol of dibromoethane were added, followed by 2 mL of anhydrous acetonitrile under air. The reaction was carried out at room temperature for 3.5 h under illumination at 395 nm. The mixture was then extracted three times with saturated sodium bicarbonate aqueous solution and ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a pale yellow solid 7b (41.9 mg, 49%). The NMR data for this compound are as follows: 1 H NMR(400MHz,Chloroform-d)δ6.16(s,1H),2.68(dd,J=16.0,4.0Hz,2H),2.58-2.46(m,2H),2.14(s,2H),2.08-2.00(m,1H),1.92(dd,J=1 2.3,4.1Hz,3H),1.77-1.69(m,5H),1.50(d,J=8.3Hz,3H),1.41(d,J=7.9Hz,1H),1.27(dd,J=17.2,11.0Hz,2H),1.15(s,5H),0.66(s,4H). 13 C NMR(101MHz,Chloroform-d)δ209.04,201.81,199.48,160.61,125.78,63.21,56.58,50.77,46.59,43.97,39.77,38.21,35.59,34.08,34.02,31.60.

[0051] Example 8:

[0052]

[0053] To a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, 0.2 mmol of cyclohexene 8a and 2 mmol of dichloroethane were added, followed by 2 mL of anhydrous acetonitrile under air. The reaction was carried out at room temperature for 12 h under illumination at 395 nm. The mixture was then extracted three times with saturated sodium bicarbonate aqueous solution and ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a colorless liquid 8b (16.3 mg, 85%). The NMR data for this compound are as follows: 1H NMR(400MHz,Chloroform-d)δ6.95-6.90(m,1H),5.94-5.91(m,1H),2.36-2.33(m,2H),2.29-2.26(m,2H),1.96-1.91(m,2H).13C NMR(101MHz,Chloroform-d)δ199.7,150.7,129.8,38.0,25.6,22.7

[0054] Example 9:

[0055]

[0056] Add 0.2 mmol of cholesterol 9a and 2 mmol of dibromoethane to a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, and then add 2 mL of anhydrous acetone under air. After reacting at room temperature for 5 h under illumination at 395 nm, extract three times with saturated sodium bicarbonate aqueous solution and ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and then concentrate under vacuum. Purify the product by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give a white solid 9b (49.6 mg, 62%). The NMR data for this compound are as follows: ¹H NMR (400 MHz, Chloroform-d) δ 5.69 (s, ¹H), 3.69–3.64 (m, ¹H), 2.53–2.49 (m, ¹H), 2.43–2.37 (m, 2H), 2.27–2.21 (m, ¹H), 2.05–1.86 (m, 5H), 1.67–1.48 (m, 8H), 1.34–1.07 (m, ¹³H), 0.93–0.85 (m, 8H), 0.68 (s, ³H); ¹³C NMR(101MHz,Chloroform-d)δ202.5,165.3,126.2,70.6,54.8,53.5,50.0,49.9,45.5,43.2,39. 6,38.7,38.4,36.4,36.3,35.8,31.2,28.6,28.1,26.4,23.9,22.9,22.6,21.3,18.9,17.4,12.1.

[0057] Example 10:

[0058] Compound 1a was used as the reference standard for reaction conditions:

[0059]

[0060] condition Reaction parameters 2a Yield (%) 1 Standard conditions (air, ambient temperature 25℃, wavelength 395nm). 96 2 Reaction under nitrogen conditions 0 3 reaction under dark conditions 0 4 Replace with 365nm / 455nm light source 56 / 23 5 reaction under pure oxygen conditions 82 6 0℃ reaction 0 7 30℃ reaction 96 8 50℃ reaction 90 9 70℃ reaction 83 10 The solvent was changed to acetone / dichloromethane / tetrahydrofuran. 89 / 0 / 76

Claims

1. A method for the selective oxidation of benzyl compounds, characterized in that: The benzyl compound was dissolved in a solvent in air, a haloalkane was added as an activating agent for molecular oxygen, and the reaction was carried out under light. After the reaction was completed, the benzyl ketone compound was obtained by separation and purification. The structure of the benzyl compound is shown below: ； The haloalkane is selected from 1,2-dibromoethane or 1,2-dichloroethane; The solvent is selected from acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, toluene, nitromethane, or tetrahydrofuran; The structures of the benzyl ketone compounds are shown below: ； The illumination wavelength is 365nm-455nm; The reaction temperature is 25-35℃.

2. The method according to claim 1, characterized in that: The amount of haloalkane added is 5-20 equivalents.

3. The method according to claim 1, characterized in that: The reaction time is 3-24 hours.

4. The method according to claim 1, characterized in that: The reaction temperature is room temperature.

5. The method according to claim 1, characterized in that: The separation and purification process involves adding a saturated sodium bicarbonate aqueous solution to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and then performing column chromatography separation.

6. The method according to claim 5, characterized in that: The eluent used in column chromatography separation and purification was petroleum ether: ethyl acetate = 20:1~1:1, v / v.

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