CN109867593B - Gamma-hydroxy ketone derivative and synthetic method thereof - Google Patents
Gamma-hydroxy ketone derivative and synthetic method thereof Download PDFInfo
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Abstract
The invention discloses a gamma-hydroxy ketone derivative and a synthesis method thereof. Styrene is taken as a raw material and is subjected to coupling reaction with alpha-bromoacetophenone under the action of a ruthenium complex and illumination to synthesize a series of gamma-hydroxyketone derivatives with different structures, and the products can be further converted into functional products. The method has the advantages of easily obtained raw materials, simple and convenient operation, mild reaction conditions and diversity of functional groups.
Description
Technical Field
The invention relates to a method for preparing a gamma-hydroxyketone derivative by visible light catalysis. Styrene which is easy to prepare, has wide sources and low price is taken as a raw material, and the hydroxyalkylation reaction of olefin is realized under the action of a ruthenium complex and under the condition of illumination, so that the gamma-hydroxyketone 1 is generated in one step. Compared with the existing synthesis method of gamma-hydroxy ketone, the method has the advantages of easily obtained raw materials, simple and convenient operation, mild reaction conditions and environmental friendliness; and the conversion of organic matters is realized by utilizing light energy, and no oxidant or reducer is required to be added, so that the method has the characteristic of high atom economy.
Background
Visible light is a cheap and abundant natural resource. Chemists currently have a wide-ranging interest in how to efficiently use visible light to effect conversion of organic compounds. In 2008, Macmillan and Yoon reported visible light catalyzed alpha enantioselective alkylation of aliphatic aldehydes (Science 2008,322,77) and [2+2] cycloaddition of unsaturated enones (j.am.soc.chem.2008,130,12886), respectively. The use of visible light catalysis in organic synthesis has received a great deal of attention from chemists afterwards.
The bifunctional of olefins is an important process for the construction of complex molecules. Previous studies have mainly focused on transition metal-catalyzed bifunctional olefins, but the application is limited by the disadvantages of often harsh reaction conditions, narrow substrate application range, etc. (eur.j.org.chem.2017,2017, 5821). However, in recent years, visible light catalysis has overcome these disadvantages of transition metal catalysis. The bifunctional of visible light catalyzed olefins has attracted considerable attention to chemists today. However, the addition of olefins by the photocatalytic generation of free radicals using halides as free radical precursors has been reported (chem. eur. j.2016,22,13794; j.org. chem.2016,81,7148; adv. synth. catal.2016,358, 1219). However, very few reports have been made on the use of halides as radical precursors to generate radicals for effecting the oxyalkylation of olefins. At present, two reports are mainly provided, one is visible light catalysis, the other is transition metal catalysis, but alpha-bromoacetonitrile is used as an alkylating agent (chem.asian.j.2015,10, 96; adv.catal.synth.2014,356,2873), and the hydroxyalkyl reaction between the alpha-bromoacetophenone and olefin is not reported when the alpha-bromoacetophenone is used as the alkylating agent.
The invention uses styrene which is easy to prepare, has wide sources and low price as raw material, and reacts with alpha-bromoacetophenone under the condition of illumination in the presence of ruthenium complex to realize the hydroxyalkylation reaction of olefin, so as to generate the gamma-hydroxy ketone derivative in one step.
Disclosure of Invention
The invention aims to synthesize the gamma-hydroxy ketone derivative by using styrene which is easy to prepare, has wide sources and low price as a raw material 2 and realizing the construction of a C-C bond and a C-O bond through one-step coupling.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the ruthenium complex is used as a catalyst, and the cross-coupling reaction of styrene 2 and alpha-bromoacetophenone 3 is carried out in the presence of light to generate the gamma-hydroxy ketone derivative 1 (reaction formula 1). And after the reaction is finished, performing product separation and characterization according to a conventional separation and purification method to obtain a target product.
The technical scheme is characterized in that:
1. substituents for styrene 2: r2Is methyl, methoxy, fluorine, chlorine, bromine, hydroxyl, cyclopropyl, trifluoromethyl, cyano, hydroxyl, ethoxycarbonyl or acetyl.
2. Substituent of α -bromoacetophenone 3: methyl, methoxy, fluoro, chloro, bromo, cyclopropyl, trifluoromethyl, cyano, hydroxy, ethoxycarbonyl or acetyl.
3. The catalyst is Ru (bpy)3Cl2·6H2O、Ru(bpy)3(PF6)2Or Ru (phen)3Cl2(ii) a Wherein the reaction is carried out with Ru (bpy)3Cl2·6H2O is the best catalyst effect, and the optimal molar ratio of the styrene 2 to the catalyst is 1: 0.02.
4. The reaction effect is best when the alkali is sodium bicarbonate.
5. The best reaction effect is achieved when the reaction solvent is acetonitrile.
6. The reaction time is 6-48 hours. Wherein the optimal reaction time is 24-48 hours.
7. The reaction temperature is 0-50 ℃, and the optimal reaction temperature is 20-40 ℃.
8. The reaction lamp source colors are white, green and blue LED lamps and white CFL lamps, the optimal reaction lamp source color is a white CFL lamp, and the optimal reaction lamp source power is 26W.
9. The preferred molar ratio of styrene 2 to α -bromoacetophenone 3 is 1: 2.
The invention has the following advantages:
1) the raw material styrene 2 has the characteristics of wide source and low price, and can be used for synthesizing gamma-hydroxyketone derivatives 1 with different types and structures.
2) The alkene hydroxyalkyl reaction can realize cross coupling through visible light catalysis, and has the characteristics of mild reaction conditions, simple operation, wide substrate application range, high atom economy and large-scale production.
3) The hydroxyalkyl alkene reaction does not need to add any oxidant or reducer.
In a word, the invention utilizes the characteristics of wide source and low price of the styrene 2 to efficiently synthesize the gamma-hydroxyketone derivatives 1 with different types and structures, the raw materials are easy to obtain, the operation is simple and convenient, the yield of the target product is high, and the derivative can be further derived.
Detailed Description
The invention takes simple styrene 2 and alpha-bromoacetophenone 3 as raw materials to carry out cross coupling reaction under the conditions of ruthenium complex and illumination (reaction formula 1).
The specific process is as follows: in a glove box styrene 2(0.3mmol), ruthenium complex (0.006 mmol), α -bromoacetophenone 3(0.6mmol), sodium bicarbonate (0.3mmol) were weighed into a 25mL branched tube, acetonitrile (3mL) and water (0.3mmol) were added under nitrogen, and reacted for 24h under 26W CFL light. After the reaction was completed, the reaction mixture was rotary-distilled under reduced pressure to remove the solvent, and then subjected to silica gel column chromatography (eluent: petroleum ether (60-90 ℃ C.)/ethyl acetate: 20:1, v/v) to obtain the objective product 1. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.
Example 1
The specific process is as follows: para-methylstyrene 2a (35mg, 0.3mmol), Ru (bpy) were weighed in a glove box3Cl2·6H2O (4mg, 0.006mmol), alpha-bromoacetophenone 3a (120mg, 0.6mmol), NaHCO3(25mg, 0.3mmol) was added to a 25mL branched tube, and acetonitrile (3mL) and water (18mg, 0.3mmol) were added under nitrogen for reaction at room temperature for 24h under illumination of a 26W white CFL lamp. After completion of the reaction, the reaction mixture was rotary-distilled under reduced pressure to remove the solvent, followed by column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate: 20:1, v/v) to give the product 1a (53mg, yield 70%) as a pale yellow liquid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 2
The specific process is as follows: in a glove box, 1a (76mg,0.3mmol) and sodium azide (20mg, 0.3mmol) were weighed into a 25mL reaction tube with a split, and placed under N23mL of 1,4-dioxane and boron trifluoride etherate (55mg, 0.39mmol) were added under protection and reacted at 90 ℃ for 4 hours. Removing the solvent by spinning, and performing column chromatography, wherein PE (60-90 ℃) and EA are 10/1 and v/v. This gave 4a as a pale yellow liquid (17mg, yield 20%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Typical compound characterization data
4-hydroxy-1, 4-diphenyl-1-butanone derivative (1a), light yellow liquid.1H NMR(400MHz, CDCl3)δ8.02–7.85(m,2H),7.58–7.48(m,1H),7.42(dd,J＝10.6,4.7Hz, 2H),7.25(d,J＝8.0Hz,2H),7.14(d,J＝7.9Hz,2H),4.77(t,J＝6.3Hz,1 H),3.08(t,J＝7.0Hz,2H),2.56(s,1H),2.33(s,3H),2.24–2.09(m,2H). 13C NMR(100MHz,CDCl3)δ200.7(s),141.5(s),137.3(s),136.9(s),133.2 (s),129.3(s),128.7(s),128.2(s),125.8(s),73.5(s),34.9(s),33.1(s),21.2(s). C17H18O2HRMS theoretical value of [ M ]]+254.1307; measured value 254.1307.
Claims (8)
1. A method for synthesizing gamma-hydroxy ketone derivatives is characterized in that: styrene 2 is used as an initial raw material, a ruthenium complex is used as a catalyst, alpha-bromoacetophenone 3 is used as an alkylating reagent, and the hydroxyalkylation reaction of olefin is realized under the condition of illumination to generate gamma-hydroxy ketone 1 in one step;
the molecular structural formula of styrene 2 is as follows,
R2is 1-5 of methyl, methoxy, fluorine, chlorine, bromine, hydroxyl, cyclopropyl, trifluoromethyl, cyano, hydroxyl, ethoxycarbonyl or acetyl, and the number of the substituent groups is 1-5;
the synthetic route is shown in the following reaction formula,
wherein R is1Selected from the following groups: 1-5 of methyl, methoxy, fluorine, chlorine, bromine, cyclopropyl, trifluoromethyl, cyano, hydroxyl, ethoxycarbonyl or acetyl, wherein the number of the substituent groups is 1-5; r2Is 1-5 of methyl, methoxy, fluorine, chlorine, bromine, hydroxyl, cyclopropyl, trifluoromethyl, cyano, hydroxyl, ethoxycarbonyl or acetyl, and the number of the substituent groups is 1-5;
the catalyst is Ru (bpy)3Cl2·6H2O、Ru(bpy)3(PF6)2Or Ru (phen)3Cl2The alkali is one or more than two of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and potassium phosphate;
the hydroxyalkyl alkene reaction does not need to add any oxidant or reducer.
2. A method of synthesis according to claim 1, characterized in that:
wherein the mol ratio of the styrene 2 to the catalyst is 1:0.005-1: 0.05; the mol ratio of the styrene 2 to the alpha-bromoacetophenone 3 is 1:1-1: 3; the reaction solvent is 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol,N, N-one or more of dimethylformamide or tetrahydrofuran; the reaction temperature is 0-50 ℃; the reaction time is 6-48 hours; the color of light required by the reaction is one or more than two of white light, blue light or green light, the power of the lamp source is 3-26W, and the volume of the adaptive reaction system is 2 mL-100 mL.
3. A method of synthesis according to claim 2, characterized in that: the catalyst in the reaction of generating 1 from styrene 2 is Ru (bpy)3Cl2·6H2O, styrene 2 and Ru (bpy)3Cl2Is 1: 0.02.
4. A method of synthesis according to claim 2, characterized in that: the base in the reaction of styrene 2 to form 1 is sodium bicarbonate.
5. A method of synthesis according to claim 2, characterized in that: the solvent in the reaction of styrene 2 to 1 is acetonitrile.
6. A method of synthesis according to claim 2, characterized in that: the reaction time in the reaction for generating 1 styrene 2 is 24-48 hours, and the reaction temperature is 20-40 ℃.
7. A method of synthesis according to claim 2, characterized in that: the lamp power in the reaction of styrene 2 to 1 was 26W, and the lamp power was a white CFL lamp.
8. A method of synthesis according to claim 2, characterized in that: the molar ratio of the styrene 2 to the bromoacetophenone 3 is 1:1-1: 3.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0592881A2 (en) * | 1992-10-05 | 1994-04-20 | Takasago International Corporation | Process for producing optically active gamma-hydroxyketones |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0592881A2 (en) * | 1992-10-05 | 1994-04-20 | Takasago International Corporation | Process for producing optically active gamma-hydroxyketones |
Non-Patent Citations (4)
| Title |
|---|
| 2,2,2-Trifluoroethylation of Styrenes with Concomitant Introduction of a Hydroxyl Group from Molecular Oxygen by Photoredox Catalysis Activated by Visible Light;Li Lun等;《Organic Letters》;20150911;第17卷(第19期);Supporting Information第S3页第2段 * |
| A metal-free transformation of alkynes to carbonyls directed by remote OH group;Chen DaoQian等;《Green Chemistry》;20160621;第18卷(第15期);第4177页表2 * |
| Chen DaoQian等.A metal-free transformation of alkynes to carbonyls directed by remote OH group.《Green Chemistry》.2016,第18卷(第15期), * |
| Reactions of aryl cyclopropyl ketones. A new synthesis of aryl tetralones;Murphy William S.等;《Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry》;19810101;第2921页左栏 * |
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