Green synthesis method of alpha-aminoketone compound based on visible light catalytic oxidation amination reaction

Abstract

The invention provides a green synthesis method of an alpha-aminoketone compound based on visible light catalytic oxidation amination reaction, and belongs to the technical field of organic chemical synthesizing.According to the method, aliphatic aldehyde and secondary amine which are low in price and easy to obtain serve as raw materials, oxygen serves as a green terminal oxidizing agent, and the alpha-aminoketone compound is synthesized under normal temperature and visible light irradiation. The alpha-aminoketone compound is efficiently synthesized in one step through oxidative amination reaction catalyzed by organic photosensitizers such as rhodamine 6G and anthraquinone. According to the method, a noble metal catalyst and a stoichiometric oxidant are abandoned, the reaction condition is mild (room temperature), the operation is simple and convenient, the substrate application range is wide, and the method shows excellent compatibility to functional groups including various complex cyclic secondary amines (such as natural product derivatives of nornicotine, cytisine and the like); compared with the prior art, the method has the advantages that important transformation from thermal activation to light activation is realized on the reaction mechanism, and a novel green way which is more economical and environment-friendly and is easy for large-scale production is provided for synthesis of alpha-aminoketone.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and in particular relates to a green synthesis method for α-amino ketone compounds based on visible light photocatalytic oxidative amination reaction. Background Technology

[0002] In the fields of organic synthesis and medicinal chemistry, α-aminoketones are a crucial core structural unit, widely found in active drug molecules such as bupropion and prasugrel, as well as various natural products. This structure is not only an important pharmacophore but also a valuable building block for the synthesis of key intermediates such as α-amino alcohols and 1,2-diamines. Therefore, developing efficient and concise synthetic methods for α-aminoketones has always been a hot topic in organic synthesis research.

[0003] Traditional synthetic strategies, such as electrophilic amination, nucleophilic substitution, and reductive amination, often involve cumbersome reaction steps, harsh conditions (strong acid / strong base, high temperature), or dependence on prefunctionalized substrates, resulting in poor atom economy and step economy, which limits their application in green synthesis and large-scale production.

[0004] To simplify the synthesis process, researchers have developed a "one-pot" strategy for the direct one-step preparation of α-aminoketones from aliphatic aldehydes and secondary amines. The most typical example is the thermally driven oxidative rearrangement reaction. For example, reference document CN 116410098A discloses the use of sodium percarbonate as a stoichiometric oxidant to achieve the conversion of aliphatic aldehydes and secondary amines at high temperatures of 95-115℃. Although this method simplifies the operation, it has inherent drawbacks: (1) high energy consumption: the reaction requires continuous high-temperature heating; (2) low atom economy: the use of a stoichiometric oxidant generates a large amount of inorganic salt waste such as sodium carbonate, and the post-processing is complex and does not conform to the principles of green chemistry; (3) limited functional group tolerance: high-temperature conditions may cause thermally sensitive functional groups (such as certain unsaturated bonds and easily racemic chiral centers) to decompose or undergo side reactions. On the other hand, although transition metal catalytic activation of oxygen has made progress, it still cannot get rid of the dependence on noble metal catalysts, and there are risks of high cost and metal residue.

[0005] In recent years, visible light photocatalytic redox reactions have utilized light energy as a driving force to achieve a series of organic transformations under mild conditions, providing a new paradigm for green synthesis. Applying visible light photocatalysis to the direct oxidative amination of aldehydes and amines can theoretically overcome the shortcomings of the aforementioned thermocatalytic systems: using room-temperature, green light energy instead of a high-temperature heat source, and using oxygen from the air as the sole oxidant instead of stoichiometric peroxides. However, achieving this transformation faces numerous challenges, including reaction pathway design, the compatibility of photosensitizers with the reaction system, and the avoidance of over-oxidation.

[0006] Therefore, the purpose of this invention is to provide a novel visible-light photocatalysis-based oxidative amination method to overcome the key technical bottlenecks of existing thermocatalytic synthesis routes for α-aminoketones, such as high energy consumption, excessive waste, and insufficiently mild conditions. The photocatalytic system successfully developed in this invention differs fundamentally from comparative literature in its reaction mechanism, achieving efficient and highly selective synthesis of α-aminoketones under green conditions of room temperature, metal-free oxidation, and oxygen, representing a significant advancement in this field. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a green synthesis method for α-amino ketone compounds based on visible light-catalyzed oxidative amination reactions. This method aims to solve the problems of high reaction temperatures, poor atom economy, and large amounts of waste generated by the use of stoichiometric oxidants in existing thermally driven oxidative rearrangement methods (such as the sodium percarbonate system).

[0008] To solve the above problems, the present invention adopts the following technical solution: A green synthesis method for α-amino ketone compounds based on visible light photocatalytic oxidative amination reaction, the method comprising the following steps: Step 1: Add fatty aldehydes, secondary amines, rhodamine 6G or anthraquinones, potassium trimethylacetate or dipotassium hydrogen phosphate, and chloroform in a molar volume ratio of (0.75~1.5) mmol : (0.5~1.0) mmol : (0.01~0.02) mmol : (0.75~1.5) mmol : (3.0~4.0) mL to a reaction vessel at room temperature under an oxygen atmosphere and mix. React under visible light induction for 16~36 hours to obtain the reaction mixture. Step 2: After purifying the reaction mixture, α-aminoketone compounds are obtained.

[0009] Further, in step 1, the fatty aldehyde is selected from propionaldehyde, hexanal, nonanal, isovaleraldehyde, tert-pentanal, phenylpropionaldehyde, phenylacetaldehyde, 4-(pyridin-4-yl)butanal, methyl 5-oxopentanoate, methyl 6-oxohexanoate, 4-(benzyloxy)butanal, 6-((tert-butyldiphenylsilyl)oxy)hexanal, 4-(1,3-dioxoisoindol-2-yl)butanal, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylic acid, olealdehyde, 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionic acid 6-oxohexanal The ester, 5-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-3-yl)oxy)pentanal, and (R)-4-((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecylhydro-1H-cyclopentane[a]phenanthrene-17-yl)pentanal.

[0010] Further, in step 1, the secondary amine is selected from dibenzylamine, bis(4-methoxybenzyl)amine, diallylamine, N-benzylethylamine, N-benzylpropyl-2-amine, N-benzylcyclopropylamine, N-benzyl-1-(pyridin-4-yl)methylamine, (R)-N-benzyl-1-phenylethanol-1-amine, (S)-N-benzyl-1-((tert-butyldiphenylsilyl)oxy)-3-phenylprop-2-amine, N-benzyl-L-phenylalanine methyl ester, N-propyl-L-phenylalanine methyl ester, (1R,4R)-4-((benzylamino)methyl)cyclohexane-1-carboxylic acid methyl ester, morpholine, (S)-3-methylmorpholine, 4,4-difluoropiperidine, (S)-methyl(piperidin-3-yl)carbamate tert-butyl ester, 4,5,6,7-tetrahydrothiophene [3,2-c]pyridine, 1-toluenesulfonylpiperazine, (S)-3-methyl-1-toluenesulfonylpiperazine, 2-(piperazin-1-yl)pyrimidine, 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, nornicotinic acid, azacycloheptane, 1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, (S)-3-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, nortropinone, and cytisine.

[0011] Furthermore, in step 2, the reaction mixture is purified by thin-layer chromatography, with the developing solvent system being ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether being 1 / 20 to 1 / 2.

[0012] Furthermore, the chemical structural formula of the compound obtained in step 2 is shown in formula (I) below: ; In equation (I), R 1 Selected from methyl, n-butyl, n-heptyl, isopropyl, tert-butyl, benzyl, phenyl, 2-(4-pyridyl)ethyl, methyl 3-propionate, methyl 4-butyrate, 2-benzyloxyethyl, N -tert-Butoxycarbonyl-4-piperidinyl, 4-(tert-Butyldiphenylsilyl ether)butyl, 2-(isoindoline-1,3-dione)ethyl, (Z)-hexadecyl-7-enyl, 4-((2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionyl)oxy)but-1-yl, 3-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadienyl[ a ]Phenanthrene-3-yl)oxy)propyl-1-yl and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecylhydro-1H-cyclopentanyl[ a At least one of phenanthrene-17-yl)isopropyl; R 2 It is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl and isopropyl; R 3 It is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl, isopropyl, cyclopropyl, pyridin-4-ylmethyl, (R)-1-phenylethyl, (S)-1-(tert-butyldiphenylsiloxy)-3-phenyl-2-propyl, (S)-2-benzyl-3-methyl ester-1-yl and ((1R,4R)-4-methyl ester cyclohexyl)methyl; R 2 and R 3The linking cyclic structure is selected from morpholine, (S)-3-methylmorpholine, 4,4-difluoropiperidine, (S)-methyl(piperidin-3-yl)carbamate tert-butyl ester, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1-toluenesulfonylpiperazine, (S)-3-methyl-1-toluenesulfonylpiperazine, 2-(piperazin-1-yl)pyrimidine, 2,7-diazaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester, nornicotinamide, aziridine heptane, 1,4-diazaspiro[3,5] At least one of the following: heptane-1-carboxylic acid tert-butyl ester, (S)-3-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, nortropinone, and cytisine.

[0013] Compared with the prior art, the present invention has the following significant advantages: (1) Green and environmentally friendly: Using oxygen as the only oxidant, no precious metal catalyst is needed (avoiding the high cost and toxicity of transition metal catalysts), the reaction system is environmentally friendly and in line with the concept of green chemistry; (2) High efficiency and simplicity: The reaction can be carried out at room temperature, using low-cost LED lamps as the light source. The operation steps are simple (no need for high temperature, high pressure or complex post-processing), which significantly reduces energy consumption and experimental costs. (3) Excellent substrate compatibility: This system is suitable for a variety of secondary amines and cyclic secondary amines with different substituents, including dibenzylamine which is easy to deprotect, monocyclic, bicyclic and polycyclic structures with different ring sizes (such as 5-7 membered rings), as well as natural products containing cyclic secondary amine structures (such as nornicotinic acid, cytisine, nortropinone, etc.), which can be efficiently converted into the corresponding α-aminoketones, covering the nitrogen-containing heterocyclic structures commonly found in medicinal chemistry; (4) Great application potential: As the core structural unit of drugs and natural products, the efficient synthesis of α-aminoketones is of great significance for drug research and development, total synthesis of natural products and industrial production of intermediates. This invention provides new technical support for the diversification of nitrogen-containing heterocyclic compounds.

[0014] In summary, this invention develops an environmentally friendly, efficient, and universal method for synthesizing α-aminoketones through a visible light-induced photocatalytic strategy, effectively overcoming the limitations of traditional methods and demonstrating significant practical value and industrial application prospects. Attached Figure Description

[0015] To more clearly illustrate the specific embodiments of the present invention, the accompanying drawings used in the description of the specific embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0016] Figure 1 This is the 1H NMR spectrum of 1-(4-(pyrimidin-2-yl)piperazin-1-yl)hexane-2-one in Example 1 of this invention; Figure 2 This is the carbon NMR spectrum of 1-(4-(pyrimidin-2-yl)piperazin-1-yl)hexane-2-one in Example 1 of this invention; Figure 3 This is the 1H NMR spectrum of 1-(4-p-toluenesulfonylpiperazin-1-yl)hexane-2-one in Example 2 of this invention; Figure 4 This is the carbon NMR spectrum of 1-(4-p-toluenesulfonylpiperazin-1-yl)hexane-2-one in Example 2 of this invention; Figure 5 This is the 1H NMR spectrum of 1-(2-(pyridin-3-yl)pyrrolidine-1-yl)hexane-2-one in Example 3 of this invention; Figure 6 This is the carbon NMR spectrum of 1-(2-(pyridin-3-yl)pyrrolidine-1-yl)hexane-2-one in Example 3 of this invention; Figure 7 This is the 1H NMR spectrum of 1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)hexane-2-one in Example 4 of this invention; Figure 8 This is the carbon NMR spectrum of 1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)hexane-2-one in Example 4 of this invention; Figure 9 This is the 1H NMR spectrum of 1-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)hexane-2-one in Example 5 of this invention; Figure 10 This is the carbon NMR spectrum of 1-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)hexane-2-one in Example 5 of this invention; Figure 11 This is the 1H NMR spectrum of methyl 5-morpholine-4-oxovalerate in Example 6 of this invention; Figure 12 This is the carbon NMR spectrum of methyl 5-morpholine-4-oxovalerate in Example 6 of this invention. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0018] This invention provides a green synthetic method for α-aminoketone compounds based on visible light-catalyzed oxidative amination. This method is environmentally friendly, efficient, and simple, overcoming key technical bottlenecks in existing thermocatalytic α-aminoketone synthesis routes, such as high energy consumption, excessive waste, and unsuitable mild conditions. It meets the demands of green chemistry, large-scale production, and medicinal chemistry for efficient synthetic strategies. The method also provides preparations with compounds possessing potential pharmaceutical and biological activities. α -Amino ketone compounds. This method includes the following steps: Step 1: Add fatty aldehydes, secondary amines, rhodamine 6G or anthraquinones, potassium trimethylacetate or dipotassium hydrogen phosphate, and chloroform in a molar volume ratio of (0.75~1.5) mmol : (0.5~1.0) mmol : (0.01~0.02) mmol : (0.75~1.5) mmol : (3.0~4.0) mL to a reaction vessel at room temperature under an oxygen atmosphere and mix. React under visible light induction for 16~36 hours to obtain the reaction mixture. Step 2: After purifying the reaction mixture, α-aminoketone compounds are obtained.

[0019] Specifically, this invention uses inexpensive aldehydes and secondary amines as raw materials, employs oxygen as the sole oxidant, and initiates a photocatalytic reaction under LED light irradiation at room temperature to efficiently synthesize α-aminoketones. Optimal reaction conditions are established by precisely controlling reaction parameters such as the light source, photosensitizer, base, and solvent. Specifically, the molar volume ratio of aliphatic aldehydes, secondary amines, rhodamine 6G or anthraquinones, potassium trimethylacetate or dipotassium hydrogen phosphate, and chloroform is (0.75~1.5) mmol : (0.5~1.0) mmol : (0.01~0.02) mm. 0.75–1.5 mmol and 3.0–4.0 mL of ol (0.75–1.5 mmol and 3.0–4.0 mL) were added to the reaction vessel in air at room temperature and mixed. The reaction was carried out under visible light in an oxygen atmosphere for 16–36 hours to obtain the reaction mixture. This system exhibits excellent compatibility with a variety of secondary amine substrates (including secondary amines with different substituents and cyclic secondary amines, such as easily deprotected dibenzylamine, cyclic secondary amines with different ring sizes, bicyclic cyclic secondary amines, and natural products containing cyclic secondary amine structures, etc.) and can be widely applied to the synthesis of nitrogen-containing heterocyclic compounds.

[0020] Specifically, the following steps are included: (1) Raw material selection: Inexpensive and readily available aldehydes (such as aliphatic aldehydes such as hexanal) are used as raw materials, and secondary amines (including secondary amines with different group substitutions and cyclic secondary amines, such as dibenzylamine which is easy to deprotect, cyclic secondary amines with monocyclic, bicyclic or polycyclic structures, such as piperidine, piperazine, pyrrolidine, morpholine and their derivatives, as well as cyclic secondary amines in natural products such as nornicotinic acid, cytisine, nortropinone, etc.) are used as amine sources; Preferably, in the above steps, the aliphatic aldehyde is selected from propionaldehyde, hexanal, nonanal, isovaleraldehyde, tert-pentanal, phenylpropionaldehyde, phenylacetaldehyde, 4-(pyridin-4-yl)butanal, methyl 5-oxopentanoate, methyl 6-oxohexanoate, 4-(benzyloxy)butanal, 6-((tert-butyldiphenylsilyl)oxy)hexanal, 4-(1,3-dioxoisoindol-2-yl)butanal, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylic acid, olealdehyde, 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionic acid 6-oxohexyl ester, 5-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadiene[] a ]Phenanthrene-3-yl)oxy)pentanal and (R)-4-((3R, 5R, 8R, 9S, 10S, 12S, 13R, 14S, 17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecylhydro-1H-cyclopentane[ a Any one of phenanthrene-17-yl)pentanal.

[0021] Preferably, in the above steps, the secondary amine is selected from dibenzylamine, bis(4-methoxybenzyl)amine, diallylamine, etc. N -Benzylethylamine, N -Benzylpropyl-2-amine, N -Benzylcyclopropylamine, N -Benzyl-1-(pyridin-4-yl)methylamine, (R)- N -Benzyl-1-phenylethanol-1-amine, (S)- N -Benzyl-1-((tert-butyldiphenylsilyl)oxy)-3-phenylprop-2-amine, N methyl benzyl-L-phenylalanine, N 1,4,4-propyl-L-phenylalanine methyl ester, (1R,4R)-4-((benzylamino)methyl)cyclohexane-1-carboxylic acid methyl ester, morpholine, (S)-3-methylmorpholine, 4,4-difluoropiperidine, (S)-methyl(piperidin-3-yl)carbamate tert-butyl ester, 4,5,6,7-tetrahydrothiopheno[3,2-] cThe following are not specified: pyridine, 1-toluenesulfonylpiperazine, (S)-3-methyl-1-toluenesulfonylpiperazine, 2-(piperazin-1-yl)pyrimidine, 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, nornicotinic acid, azacycloheptane, 1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, (S)-3-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, nortropinone, and cytisine.

[0022] (2) Reaction conditions: oxygen is used as the sole oxidant, the reaction is carried out at room temperature (20-30 ℃), and LED lamps (10-30 W LED lamps) are used as the light source; Preferably, in the above steps, the mixed product further includes a solvent, wherein the solvent is chloroform; wherein, the fatty aldehyde, secondary amine, rhodamine 6G or anthraquinone, potassium trimethylacetate or dipotassium hydrogen phosphate, and chloroform are added to the reaction vessel at a molar volume ratio of (0.75~1.5) mmol: (0.5~1.0) mmol: (0.01~0.02) mmol: (0.75~1.5) mmol: (3.0~4.0) mL at room temperature under an oxygen atmosphere for mixing, and reacted for 16~36 hours under visible light induction to obtain the mixed product.

[0023] (3) Construction of photocatalytic system: The photocatalytic efficiency is optimized by screening photosensitizers (such as organic dye photosensitizers, specifically Rhodamine 6G, Rhodamine B, anthraquinone, eosin Y, etc.), adjusting the alkalinity of the reaction system (such as adding inorganic or organic bases such as potassium carbonate, potassium trimethylacetate, dipotassium hydrogen phosphate, triethylamine, etc.), and selecting polar aprotic solvents (such as chloroform, acetonitrile, tetrahydrofuran or dimethyl sulfoxide, etc.). (4) Reaction implementation: Fatty aldehyde, secondary amine, photocatalyst (Rhodamine 6G or anthraquinone), alkaline additive (potassium trimethylacetate or dipotassium hydrogen phosphate), and solvent (chloroform) are mixed in proportion and stirred under LED light source irradiation. After the reaction is completed, the α-amino ketone product is obtained by conventional post-treatment such as column chromatography. In the above steps, the reaction mixture is purified by thin-layer chromatography, with the developing solvent system being ethyl acetate / petroleum ether (one drop of triethylamine), and the volume ratio of ethyl acetate to petroleum ether being 1 / 10 to 1 / 2.

[0024] The chemical structural formula of the obtained compound is shown in formula (I) below: ; In equation (I), R1 Selected from methyl, n-butyl, n-heptyl, isopropyl, tert-butyl, benzyl, phenyl, 2-(4-pyridyl)ethyl, methyl 3-propionate, methyl 4-butyrate, 2-benzyloxyethyl, N -tert-Butoxycarbonyl-4-piperidinyl, 4-(tert-Butyldiphenylsilyl ether)butyl, 2-(isoindoline-1,3-dione)ethyl, (Z)-hexadecyl-7-enyl, 4-((2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionyl)oxy)but-1-yl, 3-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadienyl[ a ]Phenanthrene-3-yl)oxy)propyl-1-yl and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecylhydro-1H-cyclopentanyl[ a At least one of phenanthrene-17-yl)isopropyl; R 2 It is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl and isopropyl; R 3 It is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl, isopropyl, cyclopropyl, pyridin-4-ylmethyl, (R)-1-phenylethyl, (S)-1-(tert-butyldiphenylsiloxy)-3-phenyl-2-propyl, (S)-2-benzyl-3-methyl ester-1-yl and ((1R,4R)-4-methyl ester cyclohexyl)methyl; R 2 and R 3 The linking cyclic structure is selected from morpholine, (S)-3-methylmorpholine, 4,4-difluoropiperidine, (S)-methyl(piperidin-3-yl)carbamate tert-butyl ester, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1-toluenesulfonylpiperazine, (S)-3-methyl-1-toluenesulfonylpiperazine, 2-(piperazin-1-yl)pyrimidine, 2,7-diazaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester, nornicotinamide, aziridine heptane, 1,4-diazaspiro[3,5] At least one of the following: heptane-1-carboxylic acid tert-butyl ester, (S)-3-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, nortropinone, and cytisine.

[0025] The method will be further explained below with reference to specific embodiments. Example 1

[0026] The compound obtained in this example is 1-(4-(pyrimidin-2-yl)piperazin-1-yl)hexane-2-one, and the specific steps are as follows: (1) Procedure: Anthraquinone (0.05 mmol), dipotassium hydrogen phosphate (1.5 mmol, 1.5 equivalent), 2-(piperazin-1-yl)pyrimidine (1.0 mmol, 1.0 equivalent), hexanal (1.5 mmol, 1.5 equivalent), and chloroform (3.0 mL) were added sequentially to a 10 mL round-bottom flask (with a built-in magnetic stirrer) in an air atmosphere. After installing an oxygen bulb to ensure a continuous oxygen supply to the system, the reaction mixture was placed directly under a 20 W green LED light source and magnetically stirred for 24 hours at room temperature (approximately 25°C).

[0027] After the reaction was monitored by TLC, the mixture was removed with ethyl acetate, and the product was separated by silica gel rapid column chromatography (petroleum ether / ethyl acetate (one drop of triethylamine) = 10:1). The product was a pale yellow oil with a yield of 66%. The chemical structure and NMR spectrum of the pale yellow oil are shown below. Figure 1 , Figure 2 As shown.

[0028] (2) Characterization: 1 H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.4 Hz, 2H), 6.47 (t, J= 4.8 Hz, 1H), 3.86 (t, J = 5.2 Hz, 4H), 3.23 (s, 2H), 2.53 (t, J = 5.2 Hz, 4H), 2.43 (t, J = 7.6 Hz, 2H), 1.60–1.53 (m, 2H), 1.35–1.27 (m, 2H), 0.90 (t,J= 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 207.5, 160.6, 156.7, 108.9, 66.5,52.3, 42.5, 39.3, 24.9, 21.3, 12.8. Examples 2-6

[0029] The compounds obtained in the following examples are for expansion of other substrates, and the preparation methods are basically the same as in Example 1. The products obtained in each example and their yields are shown below: Example 2: In this example, the compound obtained was 1-toluenesulfonylpiperazine reacted with hexanal to produce 1-(4-p-toluenesulfonylpiperazine-1-yl)hexane-2-one, with a yield of 68%. Its chemical structure and NMR spectrum are shown below. Figure 3 , Figure 4 As shown.

[0030] Example 3: In this example, the compound obtained was 3-(pyrrolidin-2-yl)pyridine, which reacted with hexanal to produce 1-(2-(pyridin-3-yl)pyrrolidin-1-yl)hexane-2-one, with a yield of 66%. Its chemical structure and NMR spectrum are shown below. Figure 5 , Figure 6 As shown.

[0031] Example 4: In this embodiment, the compound obtained was (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane reacted with hexanal to generate 1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)hexane-2-one, with a yield of 72%. Its chemical structure and NMR spectrum are shown below. Figure 7 , Figure 8 As shown.

[0032] Example 5: In this embodiment, the compound obtained was 8-oxa-3-azabicyclo[3.2.1]octane reacted with hexanal to generate 1-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)hexane-2-one, with a yield of 75%. Its chemical structure and NMR spectrum are shown below. Figure 9 , Figure 10 As shown. 6:

[0033] In this embodiment, the compound obtained was methyl 5-morpholine-4-oxovalerate ester, which was formed by the reaction of morpholine and methyl 5-oxovalerate with a yield of 89%. Its chemical structure and NMR spectrum are shown below. Figure 11 , Figure 12 As shown. Examples 7-23

[0034] Examples 7-23 are basically the same as Example 1 above, except that the types of aliphatic aldehydes and secondary amines differ as shown in Table 1 below: Table 1 Comparison of differences

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] Comparative Example Compared with the prior art reference document CN 116410098 B, the prior art uses sodium percarbonate as a stoichiometric oxidant: In a 10 mL sealed tube, sodium percarbonate (0.50 mmol, 0.0786 g, 1.0 equivalent), 2-(piperazin-1-yl)pyrimidine (0.50 mmol, 1.0 equivalent), n-hexanal (1.0 mmol, 0.1002 g, 2.0 equivalent), and solvents chloroform (1.5 mL) and dichloromethane (0.5 mL) are added sequentially. The mixture is stirred at 105 °C for 24 hours. After the reaction is completed by TLC monitoring, the mixture is removed with ethyl acetate, and the product is separated by silica gel rapid column chromatography (petroleum ether / ethyl acetate (one drop of triethylamine) = 10:1). The product is a pale yellow oil with a yield of 41%.

[0042] The key differences between this example and existing technologies are shown in Table 2: Table 2. Improvements of this embodiment

[0043]

[0044] In summary, compared with existing technologies, this method eliminates the need for precious metal catalysts and stoichiometric oxidants. Compared with prior art CN 116410098 B, this method offers milder reaction conditions (room temperature), simpler operation, and a wider range of applicable substrates. It also exhibits excellent compatibility with functional groups including various complex cyclic secondary amines (such as nornicotinic acid, cytisine, and other natural product derivatives). Compared with existing technologies, this method achieves a significant shift in reaction mechanism from thermal activation to photoactivation, providing a more economical, environmentally friendly, and easily scaled-up green route for the synthesis of α-aminoketones.

[0045] The present invention has been described in detail above through embodiments, but the content described is only a preferred embodiment of the present invention and should not be considered as limiting the scope of the present invention. All equivalent changes and improvements made within the scope of the present invention should still fall within the patent coverage of the present invention.

Claims

1. A green synthesis method for α-amino ketone compounds based on visible light-catalyzed oxidative amination reaction, characterized in that: The method includes the following steps: Step 1: Add fatty aldehydes, secondary amines, rhodamine 6G or anthraquinones, potassium trimethylacetate or dipotassium hydrogen phosphate, and chloroform in a molar volume ratio of (0.75~1.5) mmol : (0.5~1.0) mmol : (0.01~0.02) mmol : (0.75~1.5) mmol : (3.0~4.0) mL to a reaction vessel at room temperature under an oxygen atmosphere and mix. Under visible light induction, react for 16~36 hours to obtain the reaction mixture. Step 2: After purifying the reaction mixture, α-aminoketone compounds are obtained.

2. The green synthesis method for α-amino ketone compounds based on visible light photocatalytic oxidative amination reaction according to claim 1, characterized in that: In step 1, the fatty aldehyde is selected from propionaldehyde, hexanal, nonanal, isovaleraldehyde, tert-pentanal, phenylpropionaldehyde, phenylacetaldehyde, 4-(pyridin-4-yl)butanal, methyl 5-oxopentanoate, methyl 6-oxohexanoate, 4-(benzyloxy)butanal, 6-((tert-butyldiphenylsilyl)oxy)hexanal, 4-(1,3-dioxoisoindol-2-yl)butanal, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylic acid, olealdehyde, 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionic acid 6-oxohexyl ester, Any one of 5-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadien[a]phenanthrene-3-yl)oxy)pentanal and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecylhydro-1H-cyclopentane[a]phenanthrene-17-yl)pentanal.

3. The green synthesis method for α-amino ketone compounds based on visible light photocatalytic oxidative amination reaction according to claim 1, characterized in that: In step 1, the secondary amine is selected from dibenzylamine, bis(4-methoxybenzyl)amine, diallylamine, N-benzylethylamine, N-benzylpropyl-2-amine, N-benzylcyclopropylamine, N-benzyl-1-(pyridin-4-yl)methylamine, (R)-N-benzyl-1-phenylethanol-1-amine, (S)-N-benzyl-1-((tert-butyldiphenylsilyl)oxy)-3-phenylpropyl-2-amine, N-benzyl-L-phenylalanine methyl ester, N-propyl-L-phenylalanine methyl ester, (1R,4R)-4-((benzylamino)methyl)cyclohexane-1-carboxylic acid methyl ester, morpholine, (S)-3-methylmorpholine, 4,4-difluoropiperidine, (S)-methyl(piperidin-3-yl)carbamate tert-butyl ester, 4,5,6,7-tetrahydrothiophene[3] [2-c]pyridine, 1-toluenesulfonylpiperazine, (S)-3-methyl-1-toluenesulfonylpiperazine, 2-(piperazin-1-yl)pyrimidine, 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester, nornicotinic acid, azacycloheptane, 1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, (S)-3-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, nortropinone, and cytisine.

4. The green synthesis method for α-amino ketone compounds based on visible light photocatalytic oxidative amination reaction according to claim 1, characterized in that: In step 2, the reaction mixture is purified by thin-layer chromatography, with the developing solvent system being ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether being 1 / 20 to 1 / 2.

5. A green synthesis method for α-amino ketone compounds based on visible light-catalyzed oxidative amination reaction according to any one of claims 1-4, characterized in that: The chemical structural formula of the compound obtained in step 2 is shown in formula (I) below: ； In equation (I), R 1 Selected from methyl, n-butyl, n-heptyl, isopropyl, tert-butyl, benzyl, phenyl, 2-(4-pyridyl)ethyl, methyl 3-propionate, methyl 4-butyrate, 2-benzyloxyethyl, N -tert-Butoxycarbonyl-4-piperidinyl, 4-(tert-Butyldiphenylsilyl ether)butyl, 2-(isoindoline-1,3-dione)ethyl, (Z)-hexadecyl-7-enyl, 4-((2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionyl)oxy)but-1-yl, 3-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadienyl[ a ]Phenanthrene-3-yl)oxy)propyl-1-yl and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecylhydro-1H-cyclopentanyl[ a At least one of phenanthrene-17-yl)isopropyl; R 2 It is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl and isopropyl; R 3 It is selected from at least one of benzyl, 4-methoxybenzyl, allyl, ethyl, isopropyl, cyclopropyl, pyridin-4-ylmethyl, (R)-1-phenylethyl, (S)-1-(tert-butyldiphenylsiloxy)-3-phenyl-2-propyl, (S)-2-benzyl-3-methyl ester-1-yl, and ((1R,4R)-4-methyl ester cyclohexyl)methyl; R 2 and R 3 The linking cyclic structure is selected from morpholine, (S)-3-methylmorpholine, 4,4-difluoropiperidine, (S)-methyl(piperidin-3-yl)carbamate tert-butyl ester, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1-toluenesulfonylpiperazine, (S)-3-methyl-1-toluenesulfonylpiperazine, 2-(piperazin-1-yl)pyrimidine, 2,7-diazaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester, nornicotinamide, aziridine heptane, 1,4-diazaspiro[3,5] At least one of the following: heptane-1-carboxylic acid tert-butyl ester, (S)-3-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester, 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, nortropinone, and cytisine.

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