Preparation method of beta-arylamino ketone
The preparation of β-arylaminoketones via electrochemical oxidation catalysis solves the problems of environmental pollution and metal residues in existing technologies, and realizes a green and efficient synthesis process.
Patent Information
- Application Number
- CN202511290947.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-10
- Publication Date
- 2026-02-10
AI Technical Summary
Existing methods for synthesizing β-aryl amino ketones present problems of environmental pollution and metal residues.
Using ketones and trimethylchlorosilane as raw materials, a nucleophilic substitution reaction was carried out under the action of an organic base and a catalyst. Subsequently, aryl tertiary amines, trimethylsilyl enol ether derivatives, electrolytes and alkaline inorganic salts were dissolved in a solvent containing acetonitrile for electrochemical oxidation catalytic reaction to prepare β-arylamino ketones.
It achieves green, sustainable, and efficient synthesis of β-aromatic amino ketones, avoiding the use of additional oxidants or reducing agents, and solving the problems of environmental pollution and metal residues.
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Figure CN121496418A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing β-arylamino ketones. Background Technology
[0002] β-Aromatic amino ketones ( As a known substance, it is a class of multifunctional pharmacophores that are widely used in the treatment of central nervous system (CNS) diseases and anti-inflammatory and immunomodulatory systems. Through its properties such as hydrogen bond donor / receptor, conformational rigidity and metabolic stability, it can significantly enhance the interaction with biological targets, becoming a key structural unit in drug design and an important component of active natural products, drugs, pesticides and other functional molecules.
[0003] Currently, the synthesis of β-aminoketones typically involves the Mannich reaction of amines, aldehydes, and olefinic carbonyl compounds, or the aza-Michael reaction using α, β-unsaturated carbonyl compounds and amines or their derivatives. However, due to the low nucleophilic activity of aromatic amines, it is difficult to obtain β-aromatic aminoketones from Mannich reactions or aza-Michael addition reactions. In recent years, cross-dehydrogenation coupling (CDC) reactions of amines have become a very attractive method for the synthesis of β-aromatic aminoketone derivatives. This method generally involves the deprotonation of a tertiary amine to form an imine intermediate, which is then further reacted with various nucleophiles. Initially, Zhang's group successfully synthesized β-aromatic aminoketone derivatives using an oxidation catalytic system constructed with Cu(I) and the oxidant TBHP. Subsequently, Sakai et al. also successfully synthesized β-aromatic aminoketone derivatives using a Co(II) / TBHP oxidation catalytic system. With the assistance of NHPI, Kobayashi's group achieved the synthesis of β-aromatic aminoketone derivatives using antimonate anions under mild aerobic oxidation conditions via a CDC reaction between an aromatic tertiary amine and a nucleophile. Zhao et al. used a visible light photoredox strategy with Ru(bpy)Cl2 to catalyze the oxidative coupling of aryl tertiary amines with trimethylsilyl enol ethers, and also obtained β-arylaminoketone derivatives. However, these methods often require the use of unstable, highly reactive oxidants or transition metal catalysts, which can lead to environmental problems and issues related to metal residues.
[0004] Therefore, there is an urgent need to develop a novel, green strategy for obtaining β-arylamine ketones to address the issues of environmental pollution and metal residues during the synthesis process. Summary of the Invention
[0005] In view of this, this application provides a method for preparing β-arylaminoketones to solve the problems of environmental pollution and metal residues during the synthesis process.
[0006] To achieve the above technical objectives, this application adopts the following technical solution: In a first aspect, this application provides a method for preparing a β-arylamino ketone, comprising the following steps: S1. Under the action of an organic base and a catalyst, a nucleophilic substitution reaction is carried out using ketones and trimethylchlorosilane as raw materials to obtain trimethylsilylenol ether derivatives; S2. An aryl tertiary amine, a trimethylsilyl enol ether derivative, an electrolyte, and an alkaline inorganic salt are dissolved in a solvent containing acetonitrile and subjected to an electrochemical oxidation catalytic reaction to obtain a β-aryl ketone.
[0007] Preferably, the temperature for the nucleophilic substitution reaction is 20-40℃.
[0008] Preferably, the organic base includes triethylamine, and the catalyst includes sodium iodide.
[0009] Preferably, the electrolyte includes one or more of tetrabutylammonium fluoroborate, lithium perchlorate, and tetrabutylammonium hexafluorophosphate.
[0010] Preferably, the alkaline inorganic salt includes one or more of sodium trifluoroacetate, sodium acetate, and sodium carbonate.
[0011] Preferably, the solvent containing acetonitrile is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 3-9:1.
[0012] Preferably, in the electrochemical oxidation catalytic reaction, the current condition is a constant current of 1-4 mA, and the reaction time is 5-20 h.
[0013] Preferably, the reaction temperature is 20-40℃, and the reaction atmosphere is either an inert atmosphere or an air atmosphere.
[0014] Preferably, in the electrochemical oxidation catalytic reaction, the anode is one or more of graphite felt and foamed carbon, and the cathode is one or more of platinum plate and carbon plate.
[0015] Preferably, the molar ratio of aryl tertiary amine to trimethylsilyl enol ether derivative is 1-1.2:3.
[0016] The beneficial effects of this application are as follows: This application synthesizes β-arylamine ketone compounds from aryl tertiary amines and trimethylsilyl enol ethers via electrochemical oxidation catalysis. Compared with traditional chemistry, the electrochemical synthesis method of this application has the advantages of being green and sustainable, highly efficient, and under mild conditions. It avoids the use of additional oxidants or reducing agents and solves the environmental pollution and metal residue problems generated by traditional methods in the synthesis of β-arylamine ketones. Attached Figure Description
[0017] Figure 1 The image shows the NMR spectrum of the product obtained in Example 1. Detailed Implementation
[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0019] This application provides a method for preparing a β-arylamino ketone, comprising the following steps: S1. Under the action of an organic base and a catalyst, a nucleophilic substitution reaction is carried out using ketones and trimethylchlorosilane as raw materials to obtain trimethylsilylenol ether derivatives; S2. An aryl tertiary amine, a trimethylsilyl enol ether derivative, an electrolyte, and an alkaline inorganic salt are dissolved in a solvent containing acetonitrile and subjected to an electrochemical oxidation catalytic reaction to obtain a β-aryl ketone.
[0020] The reaction process in step S1 is shown in equation (1): Equation (1); In formula (1), R1 is an alkyl or aromatic group, and R2 is an alkyl or aromatic group; In step S1, the ketone includes, but is not limited to, one or more of acetophenone, p-methylacetophenone, p-methoxyacetophenone, p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, 1-(2-thienyl)acetophenone, cyclopentanone, and cyclohexanone.
[0021] The reaction process in step S2 is shown in equation (2): Equation (2); In formula (2), R1 is one of alkyl, halogen, and aromatic groups; R2 is one of alkyl or aromatic groups, and at least one of R1 and R2 is an aromatic group; R3 is one of alkyl or aromatic groups; R4 is one of alkyl or aromatic groups; R3 in formula (2) is equivalent to R1 in formula (1), and R4 in formula (2) is equivalent to R2 in formula (2).
[0022] In step S2, the aromatic tertiary amine includes, but is not limited to, one or more of the following: 1,1N,N-dimethyl-p-toluidine, N,N-dimethyl-o-toluidine, N,N-dimethyl-m-toluidine, N,N-dimethyl-p-bromoaniline, N,N-dimethyl-p-chloroaniline, N,N-dimethyl-p-fluoroaniline, N,N-dimethyl-p-methoxyaniline, N,N-dimethyl-p-tert-butylaniline, ethyl 4-dimethylaminobenzoate, N-methyldiphenylamine, and N-ethyl-N-methylaniline.
[0023] The resulting β-arylaminoketones include, but are not limited to, the following structures:
[0024] In some embodiments, the nucleophilic substitution reaction is carried out at a temperature of 20-40°C.
[0025] In some embodiments, the organic base includes triethylamine, and the catalyst includes sodium iodide.
[0026] In some embodiments, the electrolyte includes one or more of tetrabutylammonium fluoroborate (nBu4NBF4), lithium perchlorate (LiClO4), and tetrabutylammonium hexafluorophosphate (nBu4NPF6).
[0027] Preferably, the electrolyte is tetrabutylfluoroborate amine, which further improves the reaction yield.
[0028] In some embodiments, the alkaline inorganic salt includes one or more of sodium trifluoroacetate (CF3COONa), sodium acetate (NaOAc), and sodium carbonate (Na2CO3).
[0029] Preferably, sodium trifluoroacetate is used as the alkaline inorganic salt, which further improves the reaction yield.
[0030] In some embodiments, the solvent containing acetonitrile is a mixture of acetonitrile (MeCN) and hexafluoroisopropanol (HFIP) in a volume ratio of 3-9:1.
[0031] Preferably, the solvent containing acetonitrile is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 4:1, which further improves the reaction yield.
[0032] In some embodiments, the electrochemical oxidation catalytic reaction is carried out under constant current conditions of 1-4 mA and reaction time of 5-20 h.
[0033] Preferably, the current condition is a constant current of 2mA and the reaction time is 10h, which further improves the reaction yield.
[0034] In some embodiments, the reaction temperature is 20-40°C, and the reaction atmosphere is either an inert atmosphere or an air atmosphere.
[0035] Preferably, the reaction atmosphere is an inert atmosphere, which further improves the reaction yield.
[0036] In some embodiments, in the electrochemical oxidation catalytic reaction, the anode is one or more of graphite felt (GF) and carbon foam (RVC), and the cathode is one or more of platinum plate (Pt) and carbon plate (C).
[0037] Preferably, the anode is a graphite felt and the cathode is a platinum plate, which further improves the reaction yield.
[0038] In some embodiments, the molar ratio of aryl tertiary amine to trimethylsilyl enol ether derivative is 1-1.2:3.
[0039] Preferably, the molar ratio of aryl tertiary amine to trimethylsilyl enol ether derivative is 1:3.
[0040] The following specific embodiments further illustrate this solution.
[0041] Example 1 A method for preparing a β-arylamino ketone includes the following steps: S1. In a 250 mL flask, acetophenone (100 mmol), pre-dried sodium iodide (18.0 g, 120 mmol), and acetonitrile (100 mL) were added and stirred until homogeneous. Then, triethylamine (16.6 mL, 120 mmol) and trimethylchlorosilane (15.2 mL, 120 mmol) were added to the reaction system. The mixture was stirred for 12 hours at room temperature (25 °C). The mixture was then treated with pre-cooled (~0 °C) hexane (100 mL) and saturated ammonium chloride (100 mL). The organic phase was collected, and the aqueous phase was extracted with hexane (2 × 50 mL). The combined organic phase was washed with ice water (2 × 50 mL) and saturated ammonium chloride (100 mL). The mixture was then dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain crude enol silyl ether. The crude enol ether was then purified by reduced pressure fractionation to obtain 1-phenyl-1-trimethylsiloxane. The reaction process is shown in formula (3). Equation (3); S2. In a single-necked flask (10 mL) equipped with a stirrer, weigh out and mix N,N-dimethylaniline (36 mg, 0.30 mmol), 1-phenyl-1-trimethylsiloxane (176 mg, 0.9 mmol), nBu4NBF4 (65.08 mg, 0.2 mmol), CF3COONa (81.61 mg, 0.6 mmol), and MeCN / HFIP (v / v=4:1, 5 mL) and add the mixture. The flask is equipped with a graphite felt electrode (10 × 10 mm). 2 As the anode, a platinum plate electrode (10 × 10 mm) 2 Using α as the cathode, the reaction mixture was electrolyzed under a nitrogen atmosphere with constant current stirring at 2 mA for 10 h. After the reaction was completed, the solution was extracted with ethyl acetate and water, the composite organic layer was dried with anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporator. Using petroleum ether and ethyl acetate as eluent (30:1), flash chromatography was performed on silica gel to obtain the pure product, which is β-arylaminoketone. The reaction process is shown in formula (4): ; The NMR spectrum of the obtained β-arylamino ketone is shown below. Figure 1 As shown.
[0042] Example 2 A method for preparing a β-arylamino ketone is the same as in Example 1, except that in step S2, sodium trifluoroacetate (CF3COONa) is replaced with sodium acetate (NaOAc).
[0043] Example 3 A method for preparing a β-arylamino ketone is the same as in Example 1, except that in step S2, sodium trifluoroacetate (CF3COONa) is replaced with sodium carbonate (Na2CO3).
[0044] Example 4 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the anode is carbon foam (RVC) and the cathode is a platinum plate (Pt).
[0045] Example 5 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the anode is a graphite felt (GF) and the cathode is a carbon plate (C).
[0046] Example 6 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the MeCN / HFIP mixed solvent is replaced with acetonitrile (MeCN).
[0047] Examples 7-8 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the volume ratio of MeCN / HFIP is 3:1 and 9:1 respectively.
[0048] Example 9 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the current intensity is 1 mA and the reaction time is 20 h.
[0049] Example 10 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the current intensity is 4 mA and the reaction time is 5 h.
[0050] Examples 11-13 A method for preparing a β-arylamino ketone is the same as in Example 1, except that in step S2, tetrabutylammonium fluoroborate (nBu4NBF4) is replaced sequentially with tetrabutylammonium perchlorate (nBu4NClO4), lithium perchlorate (LiClO4), and tetrabutylammonium hexafluorophosphate (nBu4NPF6).
[0051] Example 14 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the inert atmosphere is replaced with an air atmosphere.
[0052] Comparative Example 1 A method for preparing a β-arylaminoketone is the same as in Example 1, except that the current is 0 mA in step S2.
[0053] Comparative Example 2 A method for preparing a β-arylamino ketone is the same as in Example 1, except that in step S2, sodium trifluoroacetate (CF3COONa) is replaced with triethylamine.
[0054] Comparative Example 3 A method for preparing a β-arylamino ketone is the same as in Example 1, except that in step S2, the MeCN / HFIP mixed solvent is replaced with acetone.
[0055] Comparative Example 4 A method for preparing a β-arylaminoketone is the same as in Example 1, except that in step S2, the MeCN / HFIP mixed solvent is replaced with dichloromethane (DCE).
[0056] Testing and Evaluation The yields of the products tested in Examples 1-14 and Comparative Examples 1-4 were shown in Table 1.
[0057] Table 1 Product Yield Results
[0058] The results above show that this application synthesizes β-arylaminoketone compounds from aryl tertiary amines and trimethylsilyl enol ethers via electrochemical oxidation catalysis. Compared with traditional chemistry, the electrochemical synthesis method of this application has the advantages of being green and sustainable, highly efficient, and under mild conditions. It avoids the use of additional oxidants or reducing agents and solves the environmental pollution and metal residue problems caused by traditional methods in the synthesis of β-arylaminoketones. Moreover, the conditions in Example 1 are the optimal conditions. The highest yield of β-arylaminoketones is obtained when the electrolyte is tetrabutylfluoroborate amine, the basic inorganic salt is sodium trifluoroacetate, the solvent is acetonitrile and hexafluoroisopropanol in a volume ratio of 4:1, the current is constant at 2mA, the reaction time is 10h, the reaction atmosphere is inert, the anode is graphite felt, and the cathode is a platinum plate.
[0059] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for preparing a β-arylamino ketone, characterized in that, Includes the following steps: S1. Under the action of an organic base and a catalyst, a nucleophilic substitution reaction is carried out using ketones and trimethylchlorosilane as raw materials to obtain trimethylsilylenol ether derivatives; S2. The aryl tertiary amine, the trimethylsilyl enol ether derivative, the electrolyte, and the alkaline inorganic salt are dissolved in a solvent containing acetonitrile and subjected to an electrochemical oxidation catalytic reaction to obtain the β-aryl ketone.
2. The preparation method according to claim 1, characterized in that, The nucleophilic substitution reaction is carried out at a temperature of 20-40℃.
3. The preparation method according to claim 1, characterized in that, The organic base includes triethylamine, and the catalyst includes sodium iodide.
4. The preparation method according to claim 1, characterized in that, The electrolyte includes one or more of tetrabutylammonium fluoroborate, lithium perchlorate, and tetrabutylammonium hexafluorophosphate.
5. The preparation method according to claim 1, characterized in that, The alkaline inorganic salt includes one or more of sodium trifluoroacetate, sodium acetate, and sodium carbonate.
6. The preparation method according to claim 1, characterized in that, The solvent containing acetonitrile is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 3-9:
1.
7. The preparation method according to claim 1, characterized in that, In the electrochemical oxidation catalytic reaction, the current condition is constant current of 1-4 mA, and the reaction time is 5-20 h.
8. The preparation method according to claim 1, characterized in that, The reaction temperature is 20-40℃, and the reaction atmosphere is either an inert atmosphere or air.
9. The preparation method according to claim 1, characterized in that, In the electrochemical oxidation catalytic reaction, the anode is one or more of graphite felt and foamed carbon, and the cathode is one or more of platinum plate and carbon plate.
10. The preparation method according to claim 1, characterized in that, The molar ratio of the aryl tertiary amine to the trimethylsilyl enol ether derivative is 1-1.2:3.