CN1629149A - A kind of phase transfer catalyzed method for synthesizing α, β-epoxy ketone compound - Google Patents

Abstract

The present invention relates to the synthesis of α, β-epoxy ketone compounds, specifically a method for synthesizing α, β-epoxy ketone compounds by phase transfer catalysis, in the presence of a phase transfer catalyst, trichloroisocyanuric acid (TCCA) is the oxidizing agent, the alkali metal hydroxide is the basic modifier, and the α, β-unsaturated ketone is the raw material, which is reacted in pure organic solvent, organic solvent-water, or water; the reaction formula is as above: substituent R ₁ and R ₂ can be alkyl groups or aryl groups; when R ₁ and/or R ₂ are aryl substituents, they can have one or more electron-donating and/or electron-withdrawing groups; the reaction After completion, the product is obtained by separating according to conventional methods. The invention has the advantages of simple and convenient operation, mild conditions, readily available raw materials, high selectivity and good yield, and the reaction solvent can be selected according to the dissolution properties of raw materials.

Description

A kind of phase transfer catalyzed synthesis α, the method for β-epoxy ketone compound

technical field

The invention relates to the synthesis of α, β-epoxy ketone compounds, in particular to a method for synthesizing α, β-epoxy ketone compounds by phase transfer catalysis.

Background technique

α, β-epoxy ketone compounds are the most widely used intermediates in organic synthesis, and both carbonyl and propylene oxide groups can be functionalized [Document: Tetrahedron: Asymmetry, 2001, 12, 2359-2383, etc.] . The carbonyl functionalization includes reduction to α, β-epoxy alcohol, reductive amination reaction, Bayer-Villiger reaction, Melwein-Pondorf-Weilay reaction, etc. And the ring-opening of the propylene oxide group by nucleophilic reagents such as sulfur, oxygen, and halogen can be used to synthesize a wide variety of compounds.

α, β-epoxy ketone building blocks can be used to synthesize bioactive compounds, such as leukotriene receptor antagonist SK&F104353 [Document: J.Org.Chem.1993, 58, 6247-6254, etc.], diltiazem and paclitaxel Taxol branched [document: J.Chem.Soc., Perkin Trans.11997, 3501-3507, etc.], galacturonic acid derivatives [document: J.Chem.Soc., Perkin Trans.1 2001, 149-153 etc.], protein kinase C agonist [Document: Tetrahedron Lett.2000, 41, 9569-9574, etc.].

At present, the conventional methods for synthesizing α, β-epoxy ketone compounds include α, β-unsaturated ketone epoxidation reaction, dyne reaction between α-halogenated ketones and aldehydes [Document: Tetrahedron Lett.1998, 39, 2145 -2148, Tetrahedron 1999, 55, 6375-6386, etc.]. The epoxidation of α, β-unsaturated ketones is the most direct method for the synthesis of α, β-epoxy ketones. Oxidants commonly used in the epoxidation of α, β-unsaturated ketones include hydrogen peroxide [document: Tetrahedron Lett.1998, 39, 7563-7566, etc.], sodium hypochlorite [document: Tetrahedron Lett. , tert-butyl hydroperoxide [document: J.Am.Chem.Soc.1997, 119, 2329-2330, etc.], etc., oxygen [document: Angew.Chem., Int.Ed.Engl.1996, 35, 1725- 1728 etc]. Although these oxidizing agents can be successfully used in the epoxidation reaction of α, β-unsaturated ketones, the oxidizing agents such as hydrogen peroxide, sodium hypochlorite, potassium hypochlorite and tert-butyl hydroperoxide generally have the disadvantages of poor stability and easy decomposition, while oxygen acts as oxygen source, a stoichiometric amount of diethylzinc promoter is required.

Contents of the invention

The object of the present invention is to provide a phase transfer catalyzed α, β-unsaturated ketone epoxidation reaction to synthesize α, β-epoxy ketone compound with mild reaction conditions and low cost.

In order to achieve the above object, the technical scheme adopted in the present invention is: in the presence of a phase transfer catalyst, using α, β-unsaturated ketones as raw materials, trichloroisocyanuric acid as an oxidizing agent, and alkali metal hydroxide inorganic bases as additives. Pure organic solvent, organic solvent-water, or react in water; the reaction formula is as follows:

Wherein: substituent R ₁ can be a kind of alkyl group or aryl group; Substituent R ₂ can be a kind of alkyl group or aryl group; Aryl substituent R ₁ and/or R ₂ can be With one or more electron-donating and/or electron-withdrawing groups; one or more electron-donating and/or electron-withdrawing groups of the aryl substituents _R1 and/or _R2 can be located at different substitution positions on the aromatic ring; oxidizing agent Generally, the amount of available chlorine is equal to or greater than the stoichiometric ratio of the raw material. Usually, the amount of trichloroisocyanuric acid is 50-500% mol of the raw material, and the same is true for the amount of alkali metal hydroxide. Usually It is 200-1000% mol of the raw material; the catalyst is usually a quaternary ammonium salt or a quaternary phosphonium salt or polyethylene glycol or their mixture, and their dosage can be 0.1-20% mol of the raw material; the solvent can completely dissolve the raw material , the molar ratio of raw material to solvent is usually: 1:1 to 1:50; the reaction can be completed usually within 0.5 to 72 hours; the reaction temperature should be above the freezing point of the reaction system, usually between -50 and 30°C ; The organic solvent is a mixture of one or more polar or non-polar inert solvents or polar solvents and non-polar solvents, wherein the polar solvents are often toluene, xylene, tetrahydrofuran, N, N'-dimethyl Formamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane, chloroform or water, etc., non-polar solvents are usually hexane or benzene, mixed solvents such as: toluene/water, xylene/water, di Chloromethane/water, Chloroform/water. Products can be separated by extraction or recrystallization or column chromatography or simple filtration and other separation methods.

The present invention has following advantage:

1. The solid oxidant trichloroisocyanuric acid is stable in nature, cheap and easy to get, and is a widely used disinfectant for swimming pools; compared with other oxidants, such as sodium hypochlorite aqueous solution, calcium hypochlorite solid, hydrogen peroxide, etc., it has high stability , convenient transportation and storage, safe and reliable use, strong oxidation ability, good selectivity, etc.; under the action of phase transfer catalyst and alkaline regulator, it shows good epoxidation ability for α, β-unsaturated ketones.

2. The reaction conditions are mild. In the presence of a phase transfer catalyst, the α, β-unsaturated ketone can be converted into α, β-epoxy ketone compound in polar, non-polar organic solvent, organic solvent/water, or pure water medium. The reaction medium (solvent) can be selected according to the dissolution properties of the reactants (raw materials); this is an incomparable advantage of other oxidants.

3. The reaction selectivity and conversion rate are high. In the present invention, under given conditions, α, β-unsaturated ketones can be converted into α, β-epoxy ketone compounds with high yield, even quantitatively, without by-products, high selectivity and good yield.

4. The operation is simple and the reaction products are easy to separate. It can be purified by separation methods such as extraction, recrystallization, column chromatography or simple filtration; the organic solvent can be recycled.

In a word, the present invention has the advantages of simple operation, mild conditions, readily available raw materials, high selectivity, good yield, and the ability to select a reaction solvent according to the dissolution properties of raw materials.

Detailed ways

The present invention is described in detail below through examples; but the present invention is not limited to the following examples.

Example 1 Synthesis of trans-2,3-epoxy-1,3-diphenylpropan-1-one by solid-liquid two-phase phase transfer catalysis

In a 100ml round bottom flask, add chalcone (2.08g, 10mmol), tetrabutylammonium bromide (322mg, 1mmol) and 30ml toluene, cool to 10°C, add solid trichloroisocyanuric acid (2.32g, 10mmol ), solid KOH (3.36, 60 mmol) was added. After the dropwise addition was completed, stirring was continued at 10° C. for 4 hours, and the end point of the reaction was detected by TLC. Warm up to room temperature, add 15ml of diethyl ether to the reaction solution, filter, wash the filtrate with water, and dry over anhydrous MgSO ₄ . The solvent was distilled off, separated by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate: 50/1), and the solvent was distilled off to obtain white crystals with a yield of 92%.

Example 2 Synthesis of trans-2,3-epoxy-1,3-diphenylpropan-1-one by solid-liquid two-phase phase transfer catalysis

The embodiment under the existence of different phase transfer catalysts is summarized as follows in tabular form: (reaction condition and step are with embodiment 1)

Table 1. Effects of different phase transfer catalysts and dosage on epoxidation reaction

No. Catalyst Catalyst dosage [%] Alkali Reaction time [hours] Yield [%]

1 PEG-4600 10 KOH 24 37

2 PEG-400 10 KOH 24 71

3 TBPB 10 KOH 24 71

4 TBPC 10 KOH 24 48

5 CTMAB 10 KOH 24 70

6 TBABS 10 KOH 3 91

7 TBAB 10 KOH 4 92

8 TBAB 5 5 KOH 4 91

9 TBAB 1 1 KOH 24 42

10 TBAB 0.1 KOH 48 40

catalyst:

PEG-4600: polyethylene glycol-4600 (polyethylene glycol-4600),

PEG-400: polyethylene glycol-400 (polyethylene glycol-400),

TBPB: Tetrabutyl phosphonium bromide,

TBPC: tetrabutyl phosphonium chloride,

CTMAB: Cetyl trimethyl ammonium bromide,

TBABS: tetrabutyl ammonium bisulfate (tetrabutyl ammonium bisulfate),

TBAB: tetrabutyl ammonium bromide.

Example 3 Synthesis of trans-2,3-epoxy-1,3-diphenylpropan-1-one by solid-liquid two-phase phase transfer catalysis

The embodiment under different reaction solvent, the kind and consumption of alkali, temperature condition is summarized as follows in tabular form: (reaction condition and step are with embodiment 1)

Table 2. Effect of reaction solvent, type and amount of base, TCCA amount, temperature on epoxidation reaction

ring

No. Solvent Alkali/[%] TCCA[%] Temperature Reaction Time Yield

[℃] [hour] [%]

11 dichloromethane KOH/600 100 0 24 73

12 xylene KOH/500 90 0 5 78

13 Toluene KOH/600 100 0 4 91

14 Toluene KOH/200 50 0 24 63

15 Toluene LiOH/600 90 0 24 38

16 Toluene NaOH/600 90 0 24 53

17 Toluene CsOH/600 90 0 24 45

18 Toluene KOH/600 67 20 24 67

19 Toluene KOH/500 100 10 4 92

20 Toluene KOH/600 100 10 4 91

21 Toluene KOH/200 100 -10 8 73

22 Toluene KOH/600 100 -10 6 87

23 Toluene KOH/600 100 -20 8 85

Example 4 Synthesis of trans-substituted-2,3-epoxy-1,3-diphenylpropan-1-one by solid-liquid two-phase phase transfer catalysis

The embodiment of different reaction substrates is summarized as follows in tabular form: (reaction condition and step are with embodiment 1)

        Table 3.TBAB Catalyzed Epoxidation Reaction

No. α, β-Unsaturated Reaction Time Yield

Carbonyls [hours] [%]

R ¹ R ²

24 C ₆ H ₅ C ₆ H ₅ 4 88

25 C ₆ H ₅ 4-CH ₃ OC ₆ H ₄ 4 85

26 4-ClC ₆ H ₄ 4-FC ₆ H ₄ 3 94

27 C ₆ H ₅ 4-FC ₆ H ₄ 5 81

28 4-NO ₂ C ₆ H ₄ C ₆ H ₅ 4 77

29 C ₆ H ₅ 4-ClC ₆ H ₄ 4 91

30 4-ClC ₆ H ₄ C ₆ H ₅ 4 93

31 2-ClC ₆ H ₄ C ₆ H ₅ 4 93

32 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 2 80

33 4-ClC ₆ H ₄ 4-CH ₃ OC ₆ H ₄ 3 72

34 3-ClC ₆ H ₅ 4-PhC ₆ H ₄ 4 88

35 3-ClC ₆ H ₅ 4-CF ₃ C ₆ H ₄ 4 91

36 4-ClC ₆ H ₅ 4-MeC ₆ H ₄ 4 93

37 3-ClC ₆ H ₄ 3-MeC ₆ H ₄ 4 89

38 4-CH ₃ OC ₆ H ₄ C ₆ H ₅ 5 0

39 2-CH ₃ OC ₆ H ₄ C ₆ H ₅ 5 0

Example 5 Synthesis of trans-2,3-epoxy-3-phenyl-1-(4-methoxyphenyl)-propan-1-one by solid-liquid two-phase phase transfer catalysis

In a 100ml round bottom flask, add tetrabutylammonium bromide (322mg, 1mmol), 30ml toluene, cool to 10°C, add solid trichloroisocyanuric acid (2.32g, 10mmol), add solid KOH (3.36, 60mmol) , and stir for 15 minutes. Trans 3-phenyl-1-(4-methoxyphenyl)-propenone (2.38 g, 10 mmol) was added, stirring was continued for 5 hours, and the end of the reaction was detected by TLC. Warm up to room temperature, add 15ml of diethyl ether to the reaction solution, filter, wash the filtrate with water, and dry over anhydrous MgSO ₄ . The solvent was distilled off and separated by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate: 50/1) to obtain white crystals with a yield of 79%.

Example 6 Synthesis of trans-2,3-epoxy-3-phenyl-1-(2-methoxyphenyl)-propan-1-one by solid-liquid two-phase phase transfer catalysis

Trans 3-phenyl-1-(2-methoxyphenyl)-propenone (2.38 g, 10 mmol), the experimental method and steps are the same as in Example 5, and the yield is 76%.

Example 7 Synthesis of trans-2,3-epoxy-1,3-diphenylpropan-1-one by liquid-liquid two-phase phase transfer catalysis

In a 100ml round bottom flask, add chalcone (2.08g, 10mmol), tetrabutylammonium bromide (322mg, 1mmol) and 30ml toluene, cool to 0°C, add solid trichloroisocyanuric acid (2.32g, 10mmol ), and 50% KOH aqueous solution (6.68 g, 60 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 0° C. for 9 hours, and the end point of the reaction was detected by TLC. The temperature was raised to room temperature, 15ml of water was added to the reaction solution, the two phases were separated, and the organic phase was dried with anhydrous MgSO ₄ . The solvent was distilled off to obtain a light yellow solid, which was recrystallized from n-hexane to obtain white crystals with a yield of 75%.

Example 8 Synthesis of trans-2,3-epoxy-1,3-diphenylpropan-1-one by phase transfer catalysis without organic solvent

At 20°C, in a 100ml round bottom flask, add cetyltrimethylammonium bromide (0.18g, 0.5mmol), 50ml of water, solid trichloroisocyanuric acid (2.32g, 10mmol), add dropwise 50% Aqueous KOH (6.68 g, 60 mmol). Chalcone (2.08 g, 10 mmol) was added, stirring was continued for 24 hours, and the end of the reaction was detected by TLC. Add 30ml of diethyl ether to the reaction solution, separate the two phases, and dry the organic phase with anhydrous MgSO ₄ . The solvent was distilled off to obtain a light yellow solid, which was recrystallized from n-hexane to obtain white crystals with a yield of 98%.

Example 9 Synthesis of trans-substituted-2,3-epoxy-1,3-diphenylpropan-1-one by phase transfer catalysis without organic solvent

The embodiment of different reaction substrates is summarized as follows in tabular form: (reaction condition and step are with embodiment 8)

         Table 4. CTMAB Catalyzed Epoxidation Reaction

Sequence α, β-unsaturation Reaction time Yield

No. Carbonyl Compounds Between [%]

[Hour]

R ¹ R ²

40 C ₆ H ₅ 4-CH ₃ OC ₆ H ₄ 24 86

41 4-ClC ₆ H ₄ 4-FC ₆ H ₄ 24 94

42 C ₆ H ₅ 4-FC ₆ H ₄ 24 95

43 4-NO ₂ C ₆ H ₄ C ₆ H ₅ 24 86

44 C ₆ H ₅ 4-ClC ₆ H ₄ 24 90

45 4-ClC ₆ H ₄ C ₆ H ₅ 24 96

46 2-ClC ₆ H ₄ C ₆ H ₅ 24 95

47 4-ClC ₆ H ₄ 4-ClC ₆ H ₄ 24 93

48 4-ClC ₆ H ₄ 4-CH ₃ OC ₆ H ₄ 24 89

49 4-CH ₃ OC ₆ H ₄ C ₆ H ₄ 24 90

50 4-CH ₃ OC ₆ H ₄ 4-ClC ₆ H ₄ 24 87

51 2-CH ₃ OC ₆ H ₄ C ₆ H ₄ 24 86

Claims (8)

1. a kind of phase-transfer catalytic synthesis α, the method for β-epoxy ketone compound is characterized in that: in the presence of phase-transfer catalyst, with trichloroisocyanuric acid (TCCA) as oxygenant, alkali metal hydroxide is alkali Sex regulator, α, β-unsaturated ketone is raw material, reacts in pure organic solvent, organic solvent-water, or water; Reaction formula is as follows: Wherein: substituents R ₁ and R ₂ can be alkyl groups or aryl groups; when R ₁ and/or R ₂ are aryl substituents, they can have one or more electron-donating and/or electron-withdrawing Group; After the reaction is completed, the product can be obtained by separating according to the conventional method. 2. according to the described phase-transfer catalytic synthesis α of claim 1, the method for β-epoxy ketone compound is characterized in that: described phase-transfer catalyst is quaternary ammonium salt, quaternary phosphonium salt, polyethylene glycol or their mixture . 3. according to claim 1, the method for synthesizing α by phase transfer catalysis, β-epoxy ketone compound is characterized in that: the consumption of said oxidant trichloroisocyanuric acid is 50～500% mol of raw material, alkali metal hydrogen The amount of the oxide is 200 to 1000% mol of the raw material; the phase transfer catalyst is 0.1 to 20% mol of the raw material; the molar ratio of the raw material to the solvent is: 1:1 to 1:50; the reaction temperature is -50 to 30°C; The reaction can be completed in 0.5-72 hours. 4. according to the described phase-transfer catalysis synthesis α of claim 3, the method for β-epoxy ketone compound is characterized in that: the consumption of described oxygenant trichloroisocyanuric acid is 50～100% mol of raw material; Phase-transfer catalyst The dosage of the raw material is 0.1-10% mole; the dosage of the inorganic base is 200-600% mole of the raw material; the reaction temperature is -20-20 DEG C. 5. according to the described phase-transfer catalytic synthesis α of claim 1, the method for β-epoxy ketone compound is characterized in that: described organic solvent is toluene, dimethylbenzene, tetrahydrofuran (THF), N, N'-dimethylformamide , dimethyl sulfoxide, dichloromethane, chloroform, water, hexane, benzene or mixtures thereof. 6. according to the described phase-transfer catalytic synthesis α of claim 1, the method for β-epoxy ketone compound is characterized in that: described aryl substituent R ₁ and/or R ₂ can be substituted with one or more electrons donating group, wherein the substituent is methyl, methoxy, phenyl, halogen or trifluoromethyl. 7. The method for synthesizing α, β-epoxy ketone compounds by phase transfer catalysis according to claim 1, characterized in that: the separation of the product can be purified by extraction, recrystallization, column chromatography or filtration. 8. according to the described phase-transfer catalytic synthesis α of claim 7, the method for β-epoxy ketone compound is characterized in that: when described reaction product is separated and purified, the solvent that is used for extraction can be selected ether, sherwood oil, normal Pentane, n-hexane or n-heptane; the solvent for recrystallization can be 60% ethanol aqueous solution, absolute ethanol, chloroform or N,N-dimethylformamide; silica gel can be used for column chromatography Pack the column with n-hexane/ethyl acetate or petroleum ether/ethyl acetate as the eluent.