One-step synthesis of p-benzylacetophenone from acetophenone
By using metal samarium and manganese chloride catalysts in N,N-dimethylacetamide solvents, a one-step reduction coupling reaction between benzyl bromide and acetophenone is realized, and p-benzyl acetophenone is efficiently synthesized, which solves the synthesis problems in the prior art, improves yield and reduces costs.
Patent Information
- Application Number
- CN202310993342.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-08
- Publication Date
- 2025-08-08
- Estimated Expiration
- 2043-08-08
AI Technical Summary
The prior art is difficult to efficiently synthesize p-benzyl acetophenone through a one-step method, especially because the meta-positional nature of acetophenone leads to difficulty in generating para-position products. In addition, traditional methods have problems such as low reaction efficiency, difficult raw materials to obtain, and complex operations.
Using metal samarium and manganese chloride as catalysts, benzyl acetophenone was subjected to a one-step reduction coupling reaction of benzyl acetophenone under mild conditions to produce p-benzyl acetophenone.
The synthesis of p-benzyl acetophenone with high yield (60-70%) was achieved, which simplified the operation steps, reduced costs, utilized my country's rich rare earth resources, and had friendly and environmentally friendly reaction conditions.
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Figure GDA0005468366860000011 
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for synthesizing p-benzylacetophenone from acetophenone in one step by using manganese salt catalyzed by samarium metal. Background Art
[0002] Benzylacetophenone (shown below) has a wide range of applications as an organic synthesis reagent. Through bromination reactions, it can be used to synthesize a variety of other bioactive substances with important medical applications. For example, p-benzylacetophenone is used as a starting material to further synthesize nitrogen-containing five-membered heterocyclic structures through reactions such as bromination, and is used as a CB2 receptor [Reference 1. Harnett, Jeremiah, WO2009071753A12009-06-11], and is also used in the medical field in the study of neurotrophic factor-related diseases or heme oxygenase inhibition [Reference 2. Ishikawa, Junichi; et al, WO2010137350A12010-12-02; Reference 3. Roman, Gheorghe; et al. ChemMedChem, 2010, 5(9), 1541-1555.]. In addition, p-benzylacetophenone and phenylhydrazine can form indole heterocycles [Reference 4. Samsoniya, Sh.A.; et al, Chemistry of Heterocyclic Compounds, 2001, 37(7), 827-833.]. Benzylacetophenone can also undergo oxidation or reduction reactions to generate a variety of useful products [for example, reference 5. Yi, Hong; et al. Chemical Communications, 2015, 51(74), 14046-14049. Reference 6. Symeonidis, Theodoros S.; et al. Photochemical & Photobiological Sciences, 2015, 14(3), 563-568.].
[0003]
[0004] Using para-halogenated acetophenone as raw material and carrying out coupling reaction with other reagents is a relatively common method for synthesizing para-benzylacetophenone [Reference 7. Hsu, Che-Ming; et al. Journal of Organic Chemistry, 2022, 87(5), 3799-3803. Reference 8. Pal, Suman; et al. Advanced Synthesis & Catalysis, 2016, 358(15), 2431-2435. Reference 9. Lee, Shao-Chi; et al. Organic Letters, 2022, 24(1), 85-89.]. A slight change is the synthesis of p-benzylacetophenone by methods similar to the Suzuki coupling reaction [Ramakrishna, V.; et al. Dalton Transactions, 2017, 46(26), 8598-8610.]. In addition, p-benzylacetophenone can also be synthesized by acylation of diphenylmethane with acetyl chloride using Friedel-Crafts acylation [Reference 10. Symeonidis, Theodoros S.; et al. Photochemical & Photobiological Sciences, 2015, 14(3), 563-568.]. It is difficult to synthesize p-benzylacetophenone directly from acetophenone in one step. The main reason is that acetophenone is a meta-directing group, which is theoretically not conducive to the formation of para-position products. This method has rarely been reported in the literature. Some literature reports on the coupling of benzyl alcohol and acetophenone under specific conditions, but the reaction effect is very poor [Reference 11. Wang, Feng; et al. Chemical Communications, 2008, (27), 3196-3198. Wang, Feng; et al. Chemistry-A European Journal, 2009, 15(3), 742-753.]. In this method, only a 15% yield of p-benzylacetophenone was obtained.
[0005] Samarium is a rare earth element. Since its introduction into organic synthesis in 1980 by French chemist Kagan, samarium diiodide has been widely used in organic synthesis. It can promote a wide range of chemical reactions and functional group transformations and has been successfully applied to the synthesis of numerous natural products [Reference 12. Szostak, M.; Fazakerley, N.J.; Parmar, D.; et al. Chemical Reviews, 2014, 114, 5959-6039]. However, samarium diiodide has some drawbacks in its use. For example, it is very sensitive to air, making long-term storage difficult and requiring it to be prepared immediately. Furthermore, as a single-electron transfer reagent, samarium diiodide only utilizes one electron during use. These factors limit its application in large-scale preparations. In comparison, metallic samarium is more stable in air, easier to handle, relatively inexpensive, and allows for more efficient use of electrons. Therefore, the direct use of metallic samarium in organic synthesis holds greater promise. my country has rich rare earth resources, accounting for more than 90% of the world's reserves. The development and utilization of rare earth resources is of great significance.
[0006] The invention discloses a method for preparing p-benzylacetophenone by directly promoting the one-step reaction of acetophenone and benzyl bromide by using metal samarium in the presence of manganese chloride. The method has not been reported in domestic and foreign literature. Summary of the Invention
[0007] The object of the present invention is to provide a simple method for preparing p-benzylacetophenone in one step by using benzyl bromide and acetophenone with N,N-dimethylacetamide (DMA) as solvent and under the promotion of metal samarium and manganese chloride.
[0008] The technical solutions of the present invention are as follows:
[0009] In the presence of manganese salt, benzyl bromide and acetophenone are reductively coupled with samarium metal in N,N-dimethylacetamide (DMA) under mild conditions to form p-benzylacetophenone. The general reaction formula is shown below:
[0010]
[0011] Where, X=Cl,Br,I
[0012] The technical solution of the present invention is as follows: benzyl bromide and acetophenone are added to N,N-dimethylacetamide, which has been previously dehydrated and dried, under stirring, and then samarium metal powder and manganese chloride powder are added in sequence. The molar ratio of samarium powder is 0.5-5 times that of acetophenone; the molar ratio of manganese chloride is 0.1-1 times that of samarium powder; and the molar ratio of N,N-dimethylacetamide is 5-50 times that of acetophenone. The reaction system is carried out under anhydrous and oxygen-free conditions.
[0013] The mixture is heated to a certain temperature and stirred until the reaction is complete. The solvent is recovered from the reaction mixture, and the residue is post-treated and separated by a chromatographic column to obtain pure p-benzylacetophenone with a yield of 60-70%.
[0014] The advantages and positive effects of the present invention are as follows: the synthetic route of the present invention is simple and efficient, and p-benzylacetophenone can be obtained through a one-step reaction, with fewer operating steps and no need to separate intermediates, which greatly simplifies the operating requirements; the p-benzylacetophenone compounds synthesized by the present invention have a high yield, a simple post-treatment process, and are easy to separate during product post-treatment; the reaction conditions of the present invention are easy to achieve, and special requirements such as strong acid, strong base, severe toxicity, light, and biocatalysis are avoided; the raw materials of the present invention are simple and easy to obtain, and the benzyl bromide and manganese salt used are low-cost, basic chemical products, and are easy to obtain, and the manganese salt is relatively environmentally friendly; the samarium metal used in the present invention is a rare earth metal, and my country's rare earth resources rank first in the world, so the effective development and utilization of rare earth metals is of great significance to my country; the solvent N,N-dimethylacetamide used in the present invention can be fully recycled and reused, thereby further reducing the reaction cost. DETAILED DESCRIPTION
[0015] The following synthetic examples are used to further illustrate the present invention but are not intended to limit the present invention.
[0016] Example 1
[0017] Add anhydrous N,N-dimethylacetamide (5 mL) to a three-necked flask, then add benzyl bromide (0.3 mL) and acetophenone (0.3 mL). Add manganese chloride (0.13 g) and samarium powder (0.3 g) in sequence under magnetic stirring. Slowly raise the temperature to 50°C under nitrogen protection and stir for 4 hours. Add 5 mL of dilute hydrochloric acid (2 mol·L -1 ) to terminate the reaction, and the reaction mixture was post-treated to obtain a crude product, which was then further purified by column chromatography to obtain p-benzylacetophenone with a yield of 67%.
[0018] Colorless oil; 1 H NMR (500MHz, Chloroform-d) δ7.88(m,2H),7.28(m,4H),7.24–7.21(m,1H),7.17(m,2H),4.02(s,2H),2.56(s,3H)ppm; 13 C NMR (125MHz, Chloroform-d) δ197.75,146.82,140.07,135.32,129.13,128.96,128.66,126.44,41.93,26.54ppm.
Claims
1. A method for synthesizing p-benzylacetophenone, characterized in that In the presence of manganese chloride, samarium metal is used to promote the one-step reaction of benzyl halide and acetophenone in N,N-dimethylacetamide to prepare p-benzylacetophenone. The preparation process includes the following steps: The benzyl halide and acetophenone are uniformly mixed in N,N-dimethylacetamide that has been previously dehydrated and dried, and then metallic samarium powder and manganese chloride powder are added in sequence. The mixture is stirred at a certain temperature under nitrogen protection until the reaction is complete. The solvent of the obtained reaction mixture is recovered, and the residue is post-treated and separated by a chromatographic column to obtain pure p-benzylacetophenone. The amount of benzyl bromide used is 0.5-5 times the molar ratio of the amount of acetophenone; the amount of samarium powder used is 0.5-5 times the molar ratio of the amount of acetophenone; the amount of manganese chloride used is 0.1-1 times the molar ratio of the amount of samarium powder; and the amount of N,N-dimethylacetamide used is 5-50 times the mass of the acetophenone.
2. A method for synthesizing p-benzylacetophenone according to claim 1, characterized in that The benzyl halide used is one or more of benzyl chloride, benzyl bromide and benzyl iodine.
3. A method for synthesizing p-benzylacetophenone according to claim 1, characterized in that The reaction temperature is 0–100°C, the reaction is a one-pot step reaction, the reaction solvent can be recycled, and the reaction yield is 60–70%.