CN111362794A - Preparation method of α -acyloxyketone compound - Google Patents

Abstract

The invention relates to a preparation method of α -acyloxy ketone compound, which comprises the steps of adding ketone compound, copper catalyst and organic silicon reagent into N, N-dialkyl amide organic solvent, reacting for 24 hours at 80 ℃ to obtain α -acyloxy ketone, using ketone compound as raw material, reacting at α -C (sp) of ketone carbonyl³) Activation of the-H bond successfully achieved an efficient, simple construction of C (sp)³) The new method of the-O bond can obtain a series of α -acyloxyketone compounds, and has the advantages of good reaction yield, wide substrate application range, simple and convenient operation and high atom and step economy of reaction.

Description

Preparation method of α -acyloxyketone compound

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of α -acyloxyketone compound.

Background

α -acyloxy ketone compound is an important intermediate in organic synthesis chemistry, α -hydroxy ketone compound after hydrolysis has wide physiological activity, can be applied to synthesis of a plurality of natural products (terpene compounds and alkaloids) and is a very important synthon, and simultaneously, the hydrolyzed α -acyloxy ketone compound also exists in a plurality of natural products and active organic compounds and is a very important structural skeleton.

The a-acyloxy ketone can be hydrolyzed to obtain a-hydroxy ketone with bioactivity. Known methods for the synthesis of a-acyloxyketones are as follows: (1) acetylation of a-bromoketones, (2) anodization of enol acetate in acetic acid and Mn (OAc)₃And a method of oxidizing ketone compounds, etc., which have problems of low yield or environmental problems.

Disclosure of Invention

The invention aims to provide a preparation method for efficiently constructing α -acyloxy ketone compounds by a one-pot method, which has the advantages of good yield, wide substrate application range and simplicity and convenience in operation.

In order to achieve the purpose, the invention provides a preparation method of α -acyloxyketone compound, which comprises the steps of adding ketone compound shown as a structure (II), copper catalyst and organic silicon reagent into N, N-dialkylamide organic solvent shown as a structural formula (III), reacting for 24 hours at 80 ℃ to obtain a final product mixture, and purifying to obtain α -acyloxyketone shown as a structural formula (I), wherein the reaction formula is as follows:

wherein, R1 is any one of hydrogen atom, alkyl, aryl, hydroxyl, amino, chlorine atom, bromine atom or iodine atom;

wherein R is²、R³Are both taken from any one of alkyl and aryl;

wherein R is⁴Is any one of hydrogen atom, alkyl, phenyl, hydroxyl or amido;

wherein R is⁵Is an alkyl group;

wherein the molar ratio of the copper catalyst to the ketone compound to the organic silicon reagent is 2:1: 1;

wherein the copper catalyst is copper bromide.

The invention takes ketone compounds as raw materials and leads the C (sp) at α th site of ketone carbonyl₃) Activation of the-H bond successfully achieved an efficient, simple construction of C (sp)₃) A novel process for the production of the-O bond, to give a series of α -acyloxyketones.

Among them, preferably, the organosilicon reagent is any one of trimethyl fluoro silane, trimethyl chlorosilane, trimethyl bromo silane, trimethyl iodo silane, trimethylsilyl trifluoromethanesulfonate, trimethyl cyano silane or trifluoromethyl trimethylsilane.

Wherein preferably, the step of purifying treatment comprises quenching, extracting, washing the organic phase, drying and separating by column chromatography in sequence on the final product mixture.

Among them, it is preferable that,

quenching: quenching with water;

and (3) extraction: ethyl acetate was used as extractant;

washing: washing with saturated saline water;

and (3) drying: drying with anhydrous sodium sulfate;

and (3) column chromatography separation: 300-400 mesh silica gel chromatographic column, wherein the eluent is a mixed solution of petroleum ether and ethyl acetate according to the volume ratio of 10 to 1.

The invention has the beneficial effects that:

1、CuBr₂activation of C (sp)³) The preparation method for efficiently constructing α -acyloxy ketone compounds by using the N, N-dialkyl amide compound shown in the structural formula (III) activated by the-H bond and the organosilicon reagent has the advantages of good reaction yield, wide substrate application range and simplicity and convenience in operation.

2. The reaction is highly atomic and step economical.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.

Example 1

A dry reaction tube was taken, and p-methyl propiophenone (29.6mg,0.2mmol), copper bromide (165.2mg,0.4mmol) and trifluoromethyl trimethylsilane (56.8mg,0.4mmol) were weighed, followed by addition of 6mL of N-dimethylformamide. After the reaction was stirred at room temperature for 24 hours, it was quenched with 10mL of water, extracted three times with ethyl acetate (10mL), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was distilled off, and finally column chromatography on silica gel (300 mesh) was performed (eluent: petroleum ether/ethyl acetate volume ratio: 10/1) to give 36.5mg of a colorless liquid in a yield of 95%.

Characterization data:

¹HNMR(500MHz,CDCl3)δ8.12(s,1H),7.85(d,J＝7.8Hz,2H),7.29(d,J＝7.8Hz,2H),6.10(q,J＝7.0Hz,1H),2.42(s,3H),1.57(d,J＝7.0Hz,3H).13CNMR(100MHz,CDCl3)δ195.3,160.0,144.7,131.6,129.6,129.0,70.6,21.7,17.2.IR(KBr):2987,2961,2360,2331,1719,1680,1605,1568,1447,1177,1129cm-1.

example 2

A dry reaction tube was taken, and 1-indanone (26.4mg,0.2mmol), copper bromide (165.2mg,0.4mmol), and trifluoromethyl trimethylsilane (56.8mg,0.4mmol) were weighed, followed by addition of 6mL of N-dimethylformamide. After the reaction was stirred at room temperature for 2 hours, it was quenched with 10mL of water, extracted three times with ethyl acetate (10mL), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was distilled off, and finally column chromatography on silica gel (400 mesh) was performed (eluent: petroleum ether/ethyl acetate volume ratio: 10/1) to give 19.4mg of a colorless liquid with a yield of 55%.

Characterization data:

¹HNMR(400MHz,CDCl3)δ8.15(s,1H),7.72(d,J＝7.7Hz,1H),7.58(t,J＝7.3Hz,1H),7.42–7.32(m,2H),5.51–5.43(m,1H),3.62(dd,J＝17.0,8.1Hz,1H),3.01(dd,J＝17.0,4.9Hz,1H).13CNMR(101MHz,CDCl3)δ198.7,159.1,149.2,135.1,133.2,127.3,125.6,123.5,72.4,32.2.IR(KBr):3431,2931,2360,1715,1608,1466,1155,997,885cm-1.

example 3

A dried reaction tube was taken, and 2-methyl-5-propionylfuran (27.6mg,0.2mmol), copper bromide (165.2mg,0.4mmol) and trifluoromethyltrimethylsilane (56.8mg,0.4mmol) were weighed, followed by addition of 6mLN, N-dimethylformamide. After the reaction was stirred at room temperature for 24 hours, it was quenched with 10mL of water, extracted three times with ethyl acetate (10mL), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was distilled off, and finally column chromatography on silica gel (350 mesh) was performed (eluent: petroleum ether/ethyl acetate volume ratio: 10/1) to give 23.5mg of a colorless liquid with a yield of 60%.

Characterization data:

¹HNMR(500MHz,CDCl3)δ7.22(d,J＝3.5Hz,1H),6.19(d,J＝3.4Hz,1H),5.70(q,J＝7.0Hz,1H),2.41(s,3H),2.14(s,3H),1.53(d,J＝7.0Hz,3H).13CNMR(100MHz,CDCl3)δ184.8,170.3,158.5,149.1,120.6,109.3,71.4,20.7,17.3,14.1.IR(KBr):3122,2992,2360,2341,1742,1682,1515,1372,1238,1040cm-1.

example 4

A dry reaction tube was taken, and 2-pentanone (17.2mg,0.2mmol), copper bromide (165.2mg,0.4mmol), and trifluoromethyl trimethylsilane (56.8mg,0.4mmol) were weighed and then 6mL of N-dimethylformamide was added. After the reaction was stirred at room temperature for 24 hours, it was quenched with 10mL of water, extracted three times with ethyl acetate (10mL), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was removed using a rotary evaporator until no solvent was distilled off, and finally column chromatography on silica gel (380 mesh) was performed (eluent: petroleum ether/ethyl acetate volume ratio: 10/1) to give 22.7mg of a colorless liquid with a yield of 55%.

Characterization data:

¹HNMR(500MHz,CDCl3)δ8.02(d,J＝7.0Hz,2H),7.52(t,J＝7.5Hz,1H),7.39(t,J＝7.7Hz,2H),5.11(dd,J＝7.7,4.8Hz,1H),2.14(s,3H),1.99–1.78(m,2H),0.99(t,J＝7.4Hz,3H).13CNMR(100MHz,CDCl3)δ204.5,165.1,132.4,128.7,128.4,127.5,79.1,28.7,25.3,22.9,8.6.

comparative example 1

The invention patent with the application number of CN201610946542.7 discloses a preparation method of α -acyloxyketone compound, alcohol and carboxylic acid raw materials are subjected to one-pot reaction under the mediation of NBS (N-bromosuccinimide) and DBU (1, 8-diazabicycloundecen-7-ene) to prepare α -acyloxyketone

The specific steps are that 1-phenylpropanol (0.136g,1mmol), benzoic acid (0.183g,1.5mmol), NBS (0.356g,2mmol) and 1, 4-dioxane (2mL) are added in turn into a 50mL round bottom flask at room temperature, stirred at 60 ℃ for 1 hour, then DBU (0.304g,2mmol) is added, the reaction is continued for 2 hours (TLC detection reaction), then the reaction is stopped, and the crude product is obtained after concentration under reduced pressure, finally the crude product is washed by a mixed eluent of petroleum ether and ethyl acetate, and the corresponding product α -acyloxyketone compound (yellow solid 0.251g, yield 99%) is obtained by flash column chromatography (silica gel column).

Comparative example 2

The invention patent with the application number of CN201610018687.0 discloses a preparation method of α -acyloxyketone compound, aromatic ketone, copper salt and organic solvent are mixed and preheated to form a mixed system, carboxylic acid and alkaline compound are mixed and then added into the mixed system for contact reaction to prepare α -acyloxyketone compound.

The method comprises the following specific steps:

1) in the presence of oxygen, 1mmol of propiophenone and 2mmol of copper bromide are dissolved in 2mL of acetonitrile, and the mixture is placed in an oil bath, and the temperature is raised to 65 ℃ for reaction for 5 hours;

2) mixing 3mmol of potassium carbonate and 1mmol of benzoic acid, adding into a reaction system, adding 4mL of acetonitrile, and continuing to react at 65 ℃ for 24 h;

3) the reaction system is filtered while hot, the filtrate is extracted by ethyl acetate after removing acetonitrile in a rotary evaporator, the organic phase is dried by anhydrous sodium sulfate after being washed for a plurality of times, and the organic phase is filtered through a column after being dried by spinning, so that the yield is 89%.

Compared with comparative example 1, the synthesis method of α -acyloxyketone compound has fewer reaction substances and fewer operation steps, and the yield of example 1 of the invention is similar to that of comparative example 1. compared with example 1, the invention has the advantages that the reaction range and the reaction range are wider, the reaction range of the invention is wider than that of comparative example 1, the invention can react with not only aromatic ketone reactants but also alkyl ketone reactants better, more importantly, the invention can not only obtain α -acyloxyketone compound, but also react with N, N-dimethylformamide to obtain α -formyloxyketone compound, the reaction of comparative example 1 can not obtain α -formyloxyketone compound, N-dimethylformamide is used as reactant and solvent, the use of solvent is reduced, the post-treatment is simpler, the substrate used by the invention is ketone, and compared with the substrate alcohol in comparative example 1, the invention is more stable, and is not easy to deteriorate and oxidize₂And DMF are cheaper, more readily available and more stable than NBS, acid and DBU in ratio 1.

Compared with comparative example 2, the method has the advantages that the required time is short, less reaction substances are used for reaction, and the yield is obviously improved compared with comparative example 2. the reactant range of the method is wider than that of comparative example 2, the method can not only react with aromatic ketone reactants, but also can react with alkyl ketone reactants, more importantly, the method not only can obtain α -acyloxy ketone compounds, but also can react with N, N-dimethylformamide to obtain α -formyloxy ketone compounds, and the reaction of comparative example 1 cannot obtain α -formyloxy ketone compounds.

In conclusion, the preparation method of the α -acyloxy ketone compound provided by the invention has the advantages of good reaction yield, wide substrate application range and simplicity and convenience in operation, and the reaction has high atom and step economy.

It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Claims (4)

1. A preparation method of α -acyloxyketone compound is characterized in that a ketone compound with a structure shown as (II), a copper catalyst and an organic silicon reagent are added into an N, N-dialkylamide organic solvent with a structural formula shown as (III) to react for 24 hours at 80 ℃ to obtain a final product mixture, and then the final product mixture is purified to obtain α -acyloxyketone with a structural formula shown as (I), wherein the reaction formula is as follows:

wherein, R1 is any one of hydrogen atom, alkyl, aryl, hydroxyl, amino, chlorine atom, bromine atom or iodine atom;

wherein R is²、R³Are both taken from any one of alkyl and aryl;

wherein R is⁴Is any one of hydrogen atom, alkyl, phenyl, hydroxyl or amido;

wherein R is⁵Is an alkyl group;

wherein the molar ratio of the copper catalyst to the ketone compound to the organic silicon reagent is 2:1: 1;

wherein the copper catalyst is copper bromide.

2. The method of claim 1, wherein the organosilicon reagent is selected from the group consisting of trimethylsilane, chlorotrimethylsilane, bromotrimethylsilane, iodotrimethylsilane, trimethylsilylate, cyanotrimethylsilane, and methyltrimethylsilane.

3. The method of claim 1, wherein the step of purifying comprises quenching, extracting, washing the organic phase, drying and separating by column chromatography.

4. The process according to claim 3, wherein the α -acyloxyketone compound is prepared by reacting a mixture of acyloxyketone compound and acyloxyketone compound,

quenching: quenching with water;

and (3) extraction: ethyl acetate was used as extractant;

washing: washing with saturated saline water;

and (3) drying: drying with anhydrous sodium sulfate;

and (3) column chromatography separation: 300-400 mesh silica gel chromatographic column, wherein the eluent is a mixed solution of petroleum ether and ethyl acetate according to the volume ratio of 10 to 1.