Method for synthesizing alkenyl amide compound under catalysis of copper

Abstract

The invention discloses a method for synthesizing an alkenyl amide compound through copper catalysis. According to the method, copper-based transition metal which is low in price and easy to obtain is used as a catalyst, silane is used as a reducing agent, and the synthesis of a target product is realized at high yield through reductive acylation and subsequent isomerization reaction between a ketoxime derivative and an acylation reagent under mild reaction conditions. The method has the advantages of mild reaction conditions, good functional group compatibility, wide substrate application range and the like. Besides, the catalyst and the reducing agent adopted in the method are low in cost, the method has remarkable economic advantages in large-scale synthesis, and a novel efficient and green method with practical value is provided for synthesis of the alkenyl amide compound.

Description

Technical Field

[0001] This invention relates to a method for synthesizing enamide compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Enamides are a class of nitrogen-containing unsaturated compounds that possess both biological activity and synthetic value. Their unique electronic structure and reactivity enable them to play an important role in medicine, organic synthesis, and functional materials. Derivatives of these compounds exhibit a variety of biological activities, including anti-inflammatory, antibacterial, and antitumor effects, and can serve as key frameworks for drug molecules to treat respiratory diseases and cancer. In synthetic chemistry, enamides are important intermediates for constructing β-substituted enamides, axially chiral molecules, and peptide bonds. They can be efficiently converted using green methods such as photocatalysis and metal catalysis, exhibiting excellent atom economy and functional group compatibility.

[0003] Professors M. Burk and Zhang Xumu reported a reduction system of iron powder / acetic anhydride / acetic acid to synthesize enamide compounds by reducing acylated ketoximes. Professor Tang Wenjun reported a system that utilizes iron powder and acetic acid to generate ferrous acetate in situ, achieving kilogram-scale synthesis of enamides. However, iron powder is easily oxidized in air, requiring the removal of the surface oxide layer before use; furthermore, stoichiometric amounts of iron powder can easily cause localized overheating of the reaction system, affecting the stable progress of the reaction (WO 99 / 18065; J.Org.Chem.1998,63,6084; J.Org.Chem.1999,64,1775; Org.Process Res.Dev.2013,17,1061). Chinese patent application (CN200480038602.0) reported the preparation of enamides by reducing acylated ketoximes with hydrogen and acid anhydride under the catalysis of noble metals (such as iridium, rhodium, etc.), but the use of noble metals significantly increases the reaction cost. Chinese patent (CN200780013686.6) uses alkylphosphine as a reducing agent to synthesize enamides via reduction acylation. However, alkylphosphine compounds have problems such as sensitivity to air and moisture, high toxicity, and harsh reaction conditions.

[0004] Given the shortcomings of existing preparation methods, developing a new method that is low-cost, has mild reaction conditions, high yield, and is suitable for large-scale synthesis of enamides has significant practical application value. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing enamide compounds that has mild reaction conditions, low production cost, wide applicability, environmental friendliness, and high yield.

[0006] The implementation process of this invention is as follows:

[0007] A method for preparing an enamide involves reacting a ketoxime of formula (I) with an acylation reagent of formula (II) in an organic solvent in the presence of a silane reducing agent and a copper catalyst to obtain an enamide of formula (III).

[0008]

[0009] Among them, R 1 R 2 R is independently selected from hydrogen, C1-C16 alkyl or substituted alkyl, C3-C12 alkenyl or substituted alkenyl, C6-C36 aryl or substituted aryl, C4-C30 heteroaryl or substituted heteroaryl; or R 1 With R 2 Forms five- to sixteen-membered rings; X is a halogen or acyl group;

[0010] The substituted alkyl, substituted alkenyl, substituted aryl, and substituted heteroaryl groups are C2-C10 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C2-C6 acyloxy groups, C1-C6 amide groups, C1-C6 alkylamino groups, C4-C12 cycloalkylamino groups, C2-C8 ester groups, halogen groups, nitro groups, cyano groups, C1-C7 sulfonyl groups, C6-C18 aryl groups, and C5-C36 saturated or unsaturated cycloalkyl groups.

[0011] The substituted heteroaryl group is a nitrogen heteroaryl, oxoheteroaryl, or thioheteroaryl.

[0012] In this invention, the amount of acylation reagent of formula (II) is 0.1 to 5 times the molar equivalent of the ketoxime derivative of formula (I), preferably 2 to 3 times the molar equivalent; the amount of copper catalyst is 0.1 to 15 mol% of the ketoxime derivative of formula (I); and the amount of reducing agent silane is 0.1 to 5 times the molar equivalent of the ketoxime derivative of formula (I), preferably 1 to 2 times the molar equivalent.

[0013] The copper catalyst described in this invention is selected from copper powder, copper oxide, copper halide salts, nitrates, or acetates, such as copper oxide, copper acetylacetonate, copper trifluoromethanesulfonate, copper sulfate, copper nitrate, copper acetate, copper trifluoroacetate, copper bromide, copper chloride, copper tetraacetonitrile hexafluorophosphate, cuprous acetate, cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide, or copper powder, preferably cuprous halide salts or cuprous acetate.

[0014] The silane reducing agent described in this invention is selected from silane, propane, butane, octylsilane, dodecylsilane, benzylsilane, trimethylsilylamine, diphenylsilane, tetramethyldisilazane, methyldimethoxysilane, diisopropylethoxysilane, dimethylphenylsilane, n-butyldimethylsilane, octyldimethylsilane, triethylsilane, triisobutylsilane, trioctylsilane, triphenylsilane, tert-butyldiphenylsilane, n-butyldimethylsilane, or polymethylhydrosiloxane.

[0015] The organic solvents used in this invention are selected from dimethyl sulfoxide, N,N-dimethylformamide, toluene, anisole, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, ethyl acetate, or acetone, with acetonitrile or 1,2-dichloroethane being preferred.

[0016] The present invention is carried out in a temperature range of 10 to 160°C, with an optimal temperature range of 80 to 120°C and a reaction time of 6 to 48 hours, with an optimal time range of 12 to 48 hours.

[0017] This invention uses copper, which is abundant and inexpensive, as a catalyst. The ketoxime of formula (I) and the acylation reagent of formula (II) undergo a reduction acylation and isomerization reaction to obtain the enamide shown in formula (III), which has a significant cost advantage. At the same time, it uses a silane reducing agent that is stable to air and water, is non-toxic and harmless, and has the advantages of simple operation, high safety and environmental friendliness. This invention has the characteristics of mild reaction conditions, simple operation, wide substrate applicability, easy large-scale production, easy product purification and high synthesis yield. Detailed Implementation

[0018] The following examples further illustrate the content of the present invention in detail, but the present invention is not limited to the examples listed. Experimental methods in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions.

[0019] Example 1: Preparation of enamide from acetophenone oxime

[0020]

[0021] To a 250 mL round-bottom flask, add acetophenone oxime (10.81 g, 0.08 mol), triethylsilane (18.58 g, 0.16 mol), acetic anhydride (16.33 g, 0.16 mol), cuprous iodide (0.46 g, 3 mol%), and acetonitrile (100 mL). Under argon protection, stir at 80 °C for 20 hours, then cool to room temperature. Add 150 mL of water and extract three times with dichloromethane (100 mL). Combine the organic phases, wash with 150 mL of sodium hydroxide solution (3%) and saturated brine, dry, and then evaporate to dryness. Recrystallize to obtain enamide crystal 1 (10.95 g, 85%).

[0022] Structural analysis: 1 H NMR (400MHz, CDCl3) δ7.43-7.35(m,5H),6.91(s,1H),5.88(s,1H),5.10(s,1H),2.14(s,3H); 13 C NMR (100MHz, CDCl3) δ169.2,140.5,138.3,128.6,126.0,102.6,24.4.

[0023] To investigate the interaction between the catalyst and the silane reducing agent, a similar preparation method was used, but without the addition of cuprous iodide catalyst, resulting in the absence of enamide 1 formation. Similarly, another comparative example involved the absence of a phenylsilane reducing agent, also resulting in the absence of enamide 1 formation.

[0024] Example 2: Preparation of enamide from phenylbutanone oxime

[0025]

[0026] To a 25 mL round-bottom flask, add phenylbutanone oxime (2.45 g, 0.015 mol), dimethylphenylsilane (4.08 g, 0.03 mol), acetic anhydride (3.06 g, 0.03 mol), cuprous iodide (0.086 g, 3 mol%), and acetonitrile (10 mL). Under argon protection, stir at 80 °C for 20 hours, then cool to room temperature. Add 15 mL of water and extract three times with dichloromethane (10 mL). Combine the organic phases, wash with 15 mL of sodium hydroxide solution (3%) and saturated brine, dry, and evaporate to dryness. Column chromatography yields enamide crystals 2 (1.99 g, 70%).

[0027] Structural analysis: 1H NMR (400MHz, CDCl3) δ7.41-7.29(m,5H),6.67(s,1H),6.30(t,J=7.5Hz,1H),2.08(t,J=7.5Hz,2H),2.03(s,3H),1.02(t,J=7.5Hz,3H); 13 C NMR (101MHz, CDCl3) δ168.7,137.3,133.3,128.9,128.6,128.3,122.2,24.6,21.6,14.7.

[0028] Example 3: Preparation of enamide from acetophenone oxime

[0029]

[0030] To a 25 mL round-bottom flask, add acetophenone oxime (1.35 g, 0.01 mol), dimethylphenylsilane (2.72 g, 0.02 mol), propionic anhydride (2.60 g, 0.02 mol), cuprous iodide (0.04 g, 2 mol%), and acetonitrile (10 mL). Under argon protection, stir at 90 °C for 20 hours, then cool to room temperature. Add 15 mL of water and extract three times with dichloromethane (10 mL). Combine the organic phases, wash with 15 mL of sodium hydroxide solution (3%) and saturated brine, dry, and evaporate to dryness. Column chromatography yields enamide crystals 3 (1.56 g, 89%).

[0031] Structural analysis: 1 H NMR (400MHz, CDCl3) δ7.40-7.31 (m, 6H), 5.79 (s, 1H), 5.04 (s, 1H), 2.26 (q, J = 7.2Hz, 2H), 1.14 (t, J = 7.2Hz, 2H); 13 C NMR (100MHz, CDCl3) δ173.0,140.5,138.3,128.4,125.9,102.3,30.3,9.5.

[0032] Example 4: Preparation of enamide from acetophenone oxime

[0033]

[0034] To a 25 mL round-bottom flask, add acetophenone oxime (1.35 g, 0.01 mol), triethylsilane (2.33 g, 0.02 mol), benzoic anhydride (4.52 g, 0.02 mol), cuprous bromide (0.07 g, 5 mol%), and acetonitrile (10 mL). Under argon protection, stir at 90 °C for 20 hours, then cool to room temperature. Add 15 mL of water and extract three times with dichloromethane (10 mL). Combine the organic phases, wash with 15 mL of sodium hydroxide solution (3%) and saturated brine, dry, and evaporate to dryness. Column chromatography yields enamide crystals 4 (1.94 g, 87%).

[0035] Structural analysis: 1 H NMR (400MHz, CDCl3) δ7.87-7.84(m,2H),7.54-7.43(m,6H),7.45-7.37(m,3H),6.08(s,1H),5.23(s,1H). 13 C NMR (100MHz, CDCl3) δ166.2,140.6,138.5,134.8,131.8,128.8,128.7,128.7,126.9,126.0,103.0.

[0036] Example 5: Preparation of enamide from 3,4-dimethylacetophenone oxime

[0037]

[0038] To a 25 mL round-bottom flask, add 1.63 g (0.01 mol) of 3,4-dimethylacetophenone oxime, 2.72 g (0.02 mol) of dimethylphenylsilane, 2.04 g (0.02 mol) of acetic anhydride, 0.01 g (1 mol%) of cuprous chloride, and 10 mL of toluene. Under argon protection, stir at 120 °C for 24 hours, then cool to room temperature. Add 15 mL of water and extract three times with 10 mL of dichloromethane. Combine the organic phases, wash with 15 mL of 3% sodium hydroxide solution and saturated brine, dry, and evaporate to dryness. Column chromatography yields 1.51 g (80%) of enamide crystals.

[0039] Structural analysis: 1 H NMR (400MHz, CDCl3) δ7.19-7.12(m,3H),6.79(s,1H),5.84(s,1H),5.05(s,1H),2.27(s,6H),2.14(s,3H); 13C NMR (100MHz, CDCl3) δ169.2,140.5,137.1,136.7,135.8,129.7,127.1,123.3,101.5,24.3,19.7,19.4.

[0040] Example 6: Preparation of enamide from 2,5-dimethylacetophenone oxime

[0041]

[0042] To a 25 mL round-bottom flask, add 1.63 g (0.01 mol) of 2,5-dimethylacetophenone oxime, 3.69 g (0.02 mol) of diphenylsilane, 2.04 g (0.02 mol) of acetic anhydride, 0.01 g (1 mol%) of cuprous chloride, and 10 mL of tetrahydrofuran. Under argon protection, stir at 100 °C for 30 hours, then cool to room temperature. Add 15 mL of water and extract three times with 10 mL of dichloromethane. Combine the organic phases, wash with 15 mL of 3% sodium hydroxide solution and saturated brine, dry, and evaporate to dryness. Column chromatography yields enamide crystals 6 (1.41 g, 75%).

[0043] Structural analysis: 1 H NMR (400MHz, CDCl3) δ7.17(s,1H),7.06(s,3H),5.97(s,1H),4.65(s,1H),2.31(s,3H),2.28(s,3H),1.95(s,3H); 13 C NMR (100MHz, CDCl3) δ168.9,140.5,138.3,135.2,132.4,130.2,129.7,129.0,102.1,24.1,20.7,18.9.

[0044] Example 7: Preparation of enamide from tetrahydronaphthone oxime

[0045]

[0046] To a 25 mL round-bottom flask, add tetrahydronaphthyl oxime (1.61 g, 0.01 mol), triethylsilane (2.33 g, 0.02 mol), acetic anhydride (2.04 g, 0.02 mol), cuprous iodide (0.06 g, 3 mol%), and 1,2-dichloroethane (10 mL). Under argon protection, stir at 100 °C for 12 hours, then cool to room temperature. Add 15 mL of water and extract three times with dichloromethane (10 mL). Combine the organic phases, wash with 15 mL of sodium hydroxide solution (3%) and saturated brine, dry, and evaporate to dryness. Column chromatography yields enamide 7 (1.72 g, 92%).

[0047] Structural analysis: 1 H NMR (400MHz, DMSO) δ9.12 (s, 1H), 7.20-7.16 (m, 4H), 6.16 (s, 1H), 2.70-2.68 (t, J = 8Hz, 2H), 2.27 (s, 2H), 2.01 (s, 3H); 13 C NMR (101MHz, DMSO) δ174.0,141.2,137.6,136.9,132.6,132.3,131.3,127.3,124.2,32.3,28.5,26.9.

[0048] Example 8: Preparation of enamide from 6-methoxy-tetrahydronaphthyl-1-one oxime

[0049]

[0050] To a 25 mL round-bottom flask, add 1.91 g (0.01 mol) of 6-methoxy-tetrahydronaphthyl-1-one oxime, 1.32 g (0.02 mol) of polymethylhydrosiloxane, 2.04 g (0.02 mol) of acetic anhydride, 0.02 g (1 mol%) of cuprous iodide, and 10 mL of 1,4-dioxane. Under argon protection, stir at 110 °C for 36 hours, then cool to room temperature. Add 15 mL of water and extract three times with 10 mL of dichloromethane. Combine the organic phases, wash with 15 mL of sodium hydroxide solution (3%) and saturated brine, dry, and evaporate to dryness. Column chromatography yields enamide 8 (1.87 g, 86%).

[0051] Structural analysis: 1 H NMR (400MHz, DMSO) δ9.05 (s, 1H), 7.14 (d, J = 8.4Hz, 1H), 6.75 (s, 2H), 6.04 (s, 1H), 3.74 (s, 3H), 2.66 (s, 2H), 2.23 (s, 2H), 2.01 (s, 3H); 13 C NMR (100MHz, DMSO) δ173.9,163.6,143.1,137.3,129.8,128.6,121.2,118.5,116.1,60.2,32.8,28.5,26.9.

[0052] Example 9: Preparation of enamide from 5-chloro-1-epoxime

[0053]

[0054] To a 25 mL round-bottom flask, add 5-chloro-1-indanone oxime (1.81 g, 0.01 mol), diphenylsilane (1.84 g, 0.01 mol), acetic anhydride (2.04 g, 0.02 mol), cuprous iodide (0.06 g, 3 mol%), and ethyl acetate (10 mL). Under nitrogen protection, the mixture is stirred at 80 °C for 48 hours, then cooled to room temperature. The mixture is washed with 15 mL of sodium hydroxide solution (3%) and saturated brine, dried, and then evaporated to dryness. Column chromatography yields enamide crystals 9 (1.61 g, 78%).

[0055] Structural analysis: 1 H NMR (400MHz, DMSO) δ9.80 (s, 1H), 7.77 (d, J = 8Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 8Hz, 1H), 6.76 (s, 1H), 3.39-3.34 (m, 2H), 2.10 (s, 3H); 13 C NMR (100MHz, DMSO) δ174.1,149.7,144.1,141.2,135.2,131.1,129.3,124.7,119.7,41.1,28.6.

[0056] Example 10: Preparation of enamide from cyclohexanone oxime

[0057]

[0058] To a 25 mL round-bottom flask, add cyclohexanone oxime (1.13 g, 0.01 mol), polymethylhydrosiloxane (1.32 g, 0.02 mol), acetic anhydride (2.04 g, 0.02 mol), cuprous iodide (0.02 g, 1 mol%), and N,N-dimethylformamide (DMF, 10 mL). Under nitrogen protection, stir at 120 °C for 24 hours, then cool to room temperature. Add dichloromethane (10 mL), wash three times with 10 mL of water, then wash with 15 mL of sodium hydroxide solution (3%) and saturated brine. Dry and evaporate to dryness. Column chromatography yields enamide crystals 10 (1.11 g, 80%).

[0059] Structural analysis: 1 H NMR (400MHz, CDCl3) δ6.31(s,1H),6.06(s,1H),2.11-2.04(m,4H),2.01(s,3H),1.70-1.65(m,2H),1.59-1.54(m,2H); 13 C NMR (100MHz, CDCl3) δ168.7,132.7,113.1,27.7,24.0,23.8,22.3,21.7.

[0060] Example 11: Enamide derivatives were prepared using different formula (I) ketoxime derivatives and formula (II) acylation reagents according to the methods described in the examples above. The results are shown in the table below.

[0061] Table 1. Examples of reactions between different (I) ketoxime derivatives and (II) acylation reagents

[0062]

[0063]

[0064]

[0065]

Claims

1. A method for preparing an enamide, characterized in that: In an organic solvent, the ketoxime of formula (I) is reacted with the acylation reagent of formula (II) in the presence of a silane reducing agent and a copper catalyst to prepare the olefin amide of formula (III). Among them, R 1 R 2 R is independently selected from hydrogen, C1-C16 alkyl or substituted alkyl, C3-C12 alkenyl or substituted alkenyl, C6-C36 aryl or substituted aryl, C4-C30 heteroaryl or substituted heteroaryl; or R 1 With R 2 Forms five- to sixteen-membered rings; X is a halogen or acyl group; The substituted alkyl, substituted alkenyl, substituted aryl, and substituted heteroaryl groups are C2-C10 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C2-C6 acyloxy groups, C1-C6 amide groups, C1-C6 alkylamino groups, C4-C12 cycloalkylamino groups, C2-C8 ester groups, halogen groups, nitro groups, cyano groups, C1-C7 sulfonyl groups, C6-C18 aryl groups, and C5-C36 saturated or unsaturated cycloalkyl groups. The substituted heteroaryl group is a nitrogen heteroaryl, oxoheteroaryl, or thioheteroaryl.

2. The preparation method according to claim 1, characterized in that: The amount of the acylation reagent of formula (II) is 0.1 to 5 molar equivalents of the ketoxime of formula (I).

3. The preparation method according to claim 1, characterized in that: The copper catalyst is selected from copper oxide, copper acetylacetone, copper trifluoromethanesulfonate, copper sulfate, copper nitrate, copper acetate, copper trifluoroacetate, copper bromide, copper chloride, copper tetraacetonitrile hexafluorophosphate, cuprous acetate, cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide, or copper powder.

4. The preparation method according to claim 3, characterized in that: The copper catalyst is selected from cuprous halide or cuprous acetate.

5. The preparation method according to claim 3, characterized in that: The amount of copper catalyst used is 0.1–15 mol of the ketoxime of formula (I).

6. The preparation method according to claim 1, characterized in that: The silane reducing agent is selected from silane, propane, butane, octylsilane, dodecylsilane, benzylsilane, trimethylsilylamine, diphenylsilane, tetramethyldisilazane, methyldimethoxysilane, diisopropylethoxysilane, dimethylphenylsilane, n-butyldimethylsilane, octyldimethylsilane, triethylsilane, triisobutylsilane, trioctylsilane, triphenylsilane, tert-butyldiphenylsilane, n-butyldimethylsilane, or polymethylhydrosiloxane.

7. The preparation method according to claim 6, characterized in that: The amount of reducing agent used is 0.1 to 5 molar equivalents of the ketoxime of formula (I).

8. The preparation method according to claim 1, characterized in that: The organic solvent used in the reaction is selected from dimethyl sulfoxide, N,N-dimethylformamide, toluene, anisole, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, ethyl acetate, or acetone.

9. The preparation method according to claim 1, characterized in that: The reaction is carried out at a temperature of 10–160°C for a time of 6–48 hours.

10. The preparation method according to claim 9, characterized in that: The reaction temperature is 80–120°C.

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