A method for photoinduced alpha-hydroxylation of beta-dicarbonyl compounds in solid phase and a solid phase photo reactor therefor

Abstract

The application discloses a kind of photoinduced beta-dicarbonyl compound alpha-hydroxylation solid-phase reaction method and its solid-phase photo reactor, belong to organic synthesis technical field.The method is with beta-dicarbonyl compound as substrate, in the presence of solid carrier, with aromatic amine as organic base catalyst, in oxygen-containing atmosphere and under visible light irradiation, at room temperature, carry out solid-phase photooxidation reaction, high selectivity, high efficiency alpha-hydroxy-beta-dicarbonyl compound is prepared.The application is simple and safe to operate, avoids the problems of using dangerous oxidant, strong base, heavy metal catalyst and a large amount of organic solvent in traditional method, reaction condition is mild, selectivity is high, environment-friendly, substrate applicability is wide, with significant industrial application prospect.A suitable solid-phase photo reactor for the above reaction is also provided.The reactor is simple in structure, easy to operate and easy to obtain.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a solid-phase synthesis method for selective α-hydroxylation of β-dicarbonyl compounds under mild conditions in a solid phase via photo-induced oxygen oxidation. Background Technology

[0002] The α-hydroxylation of β-dicarbonyl compounds is an important class of organic reactions, and the resulting α-hydroxy-β-dicarbonyl structures are widely found in natural products, drug molecules, and functional materials, exhibiting significant bioactivity and synthetic value. Traditional α-hydroxylation methods mainly rely on metal catalysts, base catalysts, or oxidants, but still face many limitations in terms of atom economy, reaction conditions, environmental friendliness, and ease of operation.

[0003] Currently, the reported catalytic systems for the oxygen oxidation of β-dicarbonyl compounds with achiral α-hydroxylation mainly include the following categories: (1) Metal catalysis: such as the SmI3 / I2 co-catalytic system, which can achieve aerobic α-hydroxylation of β-keto esters and amides under mild and alkaline conditions, but its metal loading is high (about 5 mol%), and the reactivity of some substrates (such as α-unsubstituted compounds) is poor. Other metals such as Pd, Au, Mn, Co, Ce, etc. can also be used in this type of reaction, but they generally have problems such as metal residue, high cost and environmental burden.

[0004] (2) Alkali-catalyzed methods: Systems such as NaOH / KF, Cs2CO3 / P(OEt)3, and AcONa / I2 can achieve α-hydroxylation under certain conditions. Among them, the NaOH system requires high temperature (120℃) and has a narrow substrate applicability; the Cs2CO3 system requires a pure oxygen atmosphere to improve the yield; although the AcONa / I2 system can be carried out in air, it is heavily dependent on light irradiation to promote the reaction, and has poor control over α-unsubstituted substrates, and is prone to over-oxidation or side reactions.

[0005] (3) Photocatalysis: In recent years, photo-induced catalysis strategies have attracted attention due to their mild conditions and environmental friendliness. For example, ethylenediamine-Cu(II) complexes can efficiently catalyze the α-hydroxylation of β-keto esters under visible light, with extremely low catalyst loading (1 mol% Cu, 0.01 mol% photosensitizer) and a yield as high as 99%. This system achieves efficient and highly selective hydroxylation by photoactivating oxygen to generate singlet oxygen, demonstrating the significant advantages of photocatalysis in this type of reaction.

[0006] While the aforementioned methods each have their own unique features, the vast majority of reactions are carried out in the liquid phase, which presents challenges such as high solvent consumption, complex post-processing, difficult product separation, and high energy consumption. Furthermore, solid-phase reactions offer significant advantages in simplifying operations, improving atom economy, promoting catalyst recovery, and reducing waste; however, there is currently no solid-phase photocatalytic method for the α-hydroxylation of β-dicarbonyl compounds.

[0007] Therefore, developing a photoinduced, solid-phase method for the α-hydroxylation of β-dicarbonyl compounds is of significant scientific importance and promising application prospects. This method holds the promise of achieving efficient, highly selective, and environmentally friendly α-hydroxylation reactions under solvent-free and mild visible light irradiation conditions, providing a new pathway for the green synthesis of related functional molecules. Summary of the Invention

[0008] The first objective of this invention is to overcome the shortcomings of the prior art and provide a highly efficient, highly selective, and environmentally friendly method for the photoinduced α-hydroxylation of β-dicarbonyl compounds in a solid-phase reaction. The second objective of this invention is to provide a solid-phase photoreactor for realizing the aforementioned photoinduced α-hydroxylation of β-dicarbonyl compounds in a solid-phase reaction.

[0009] The technical solution of the present invention: A photo-induced solid-phase reaction method for α-hydroxylation of β-dicarbonyl compounds includes the following steps: uniformly mixing β-dicarbonyl compound reactants, catalysts, and solid supports in a reactor, and carrying out a solid-phase reaction under visible light irradiation and room temperature conditions in an oxygen-containing atmosphere to obtain α-hydroxy-β-dicarbonyl compounds; the reaction equation is as follows; In the formula, R1 is a group at different substitution positions on the benzene ring, and the group is hydrogen, methyl, methoxy or halogen; n is 1 or 2; X is O or NH; R2 is methyl, ethyl, tert-butyl or adamantyl.

[0010] Furthermore, the catalyst is an inorganic base catalyst, a phase transfer catalyst, or an organic base catalyst; preferably an organic base catalyst.

[0011] Furthermore, the inorganic base catalyst is potassium carbonate, potassium bicarbonate, or cesium carbonate. The phase transfer catalyst is tetrabutylammonium iodide, tetrabutylammonium chloride, or tetrabutylammonium bromide. The organic base catalyst is sodium methoxide, potassium tert-butoxide, n-butylamine, diethylamine, triethylamine, aniline, diphenylamine, triphenylamine, bis(4-methoxyphenyl)amine, 4-methoxy-N-phenylaniline, 4-nitrodiphenylamine, N-phenyl-1-naphthylamine, or N,N-diphenyl-p-phenylenediamine. Aromatic amine compounds are preferred, and diphenylamine is most preferred.

[0012] Furthermore, the solid support serves to disperse reactants, provide a larger specific surface area to promote mass transfer, and may affect reaction selectivity by absorbing moisture generated during the reaction. It is at least one of silica gel (SiO2), titanium silicate molecular sieve (TS-1), anhydrous magnesium sulfate (Na2SO4, anhydrous), silicon carbide (SiC), carbon nitride (NC), 4A molecular sieve, and nano-alumina (nano-Al2O3). Preferably, it is a mixed support of 4A molecular sieve and silica gel. When using a mixed support of 4A molecular sieve and silica gel, the mixed support can significantly improve the conversion rate and selectivity of the reaction. The mass ratio of 4A molecular sieve to silica gel is 1:1 to 4:1, preferably 2:1.

[0013] Furthermore, the substrate of the β-dicarbonyl compound is a β-ketoester or a β-diketone.

[0014] Furthermore, after the reaction in the reactor is completed, the target α-hydroxy-β-dicarbonyl compound can be obtained by organic solvent extraction or column chromatography separation.

[0015] Furthermore, the wavelength of the light source is any wavelength within the range of 365–760 nm. Preferably, it is a white light source (full wavelength). Most preferably, it is a white LED lamp, which can effectively excite the reaction system while providing moderate energy, which is beneficial for controlling side reactions.

[0016] Furthermore, the oxygen-containing atmosphere is air or an oxygen atmosphere.

[0017] Furthermore, the reaction time is 1-12 h, preferably 1-6 h.

[0018] Furthermore, the amount of catalyst used is 0.1-1 equivalent of the molar amount of the β-dicarbonyl compound reactant, preferably 0.1-0.5 equivalent. Most preferably, it is 0.1 equivalent.

[0019] A solid-phase photoreactor for photo-induced α-hydroxylation of β-dicarbonyl compounds includes a connector 1, a support frame 2, a gas storage chamber 3, an external rotary drive unit 4, a light source 5, a reaction flask 6, and a magnetic stirrer 7. The connector 1 is provided with three interfaces: an interface for connecting to an oxygen source, an interface for connecting to the gas storage chamber 3, and an interface for connecting to a vacuum pump. The gas storage chamber 3 is a sealed hollow structure with two interfaces: one connected to connector 1, and the other connected to the external rotary drive unit 4. The gas storage chamber 3 has both gas storage and pressure buffering functions, which can maintain stable gas pressure during the filling and discharging process and ensure that the reaction atmosphere is uniform and controllable.

[0020] The support frame 2 is used to fix the gas storage chamber 3.

[0021] The two ends of the external rotary drive unit 4 are respectively connected to the gas storage chamber 3 and the reaction bottle 6 interface. The internal motor can drive the reaction bottle 6 to rotate mechanically. The internal motor provides stable and adjustable rotational power to ensure that the solid reactant is uniformly irradiated during the reaction process.

[0022] The reaction flask 6 is used to hold the magnetic stir bar, β-dicarbonyl compound reactants, catalyst, and solid support.

[0023] The magnetic stirrer 7 is placed at the bottom of the reaction flask 6.

[0024] The light source 5 is positioned above the reaction flask 6.

[0025] Furthermore, the storage medium for the oxygen source is a gas bag or a depressurized gas cylinder; it can be filled with different types of gases (such as nitrogen, argon, oxygen, etc.) to flexibly adjust the reaction atmosphere according to experimental needs.

[0026] Furthermore, the vacuum pump interface facilitates vacuuming and inert gas replacement in the solid-phase photoreactor.

[0027] Furthermore, valves are provided at the three interfaces of the connector 1.

[0028] Furthermore, the support frame 2 is equipped with a multi-directional adjustment mechanism, which can achieve precise positioning of the gas storage chamber 3 in the horizontal and vertical directions, making it easier to align the reaction bottle 6 with the optical path.

[0029] Furthermore, the reaction flask 6 is made of high-transmittance glass or quartz material, and different volumes of flasks can be replaced according to the experimental scale to accommodate solid-phase reactions ranging from milligrams to grams. The external rotation drive unit 4 drives the reaction flask 6 to rotate mechanically through its internal motor, ensuring that the reaction flask and its internal solid-phase material can be uniformly illuminated by the light source 5. Furthermore, the magnetic stirrer 7 is used to drive the magnetic stir bar inside the reaction flask 6 to enhance the mixing of solid materials.

[0030] Furthermore, the light source 5 is fixed on the platform of the magnetic stirrer 7, and can be continuously raised and lowered in the vertical direction through a movable clamp, thereby precisely controlling the distance between the light source 5 and the reaction flask 6 and adjusting the light intensity.

[0031] Furthermore, the reaction flask 6 is rotated by a motor (0-500 r / min) on one hand, and the reactants in the reaction flask 6 are magnetically stirred by a magnetic stirrer 7 (0-2000 r / min) on the other hand, and the reactants in the reaction flask react through dual rotation stirring.

[0032] The beneficial effects of this invention are: (1) Green and environmentally friendly: The reaction is in solid phase, which greatly reduces the use of organic solvents; air oxygen is used as a green oxidant; no transition metal catalyst is required.

[0033] (2) Mild and safe conditions: It is carried out at room temperature and normal pressure, without the need for high temperature, high pressure or strong corrosive reagents, and the operation is highly safe.

[0034] (3) High selectivity and high efficiency: It can achieve a conversion rate of more than 99% and a selectivity of more than 97% for the model substrate, and the reaction time is short.

[0035] (4) Solid-phase photoreactors have a simple structure, are easy to operate, and are readily available. Attached Figure Description

[0036] Figure 1 This is a schematic diagram of the solid-phase reactor for the photoinduced α-hydroxylation of β-dicarbonyl compounds according to the present invention.

[0037] In the diagram: 1 Connector; 2 Support frame; 3 Gas storage chamber; 4 External rotary drive unit; 5 Light source; 6 Reaction flask; 7 Magnetic stirrer. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. However, this should not be construed as limiting the scope of the above-described subject matter of this invention to the following embodiments.

[0039] Example 1: Solid-phase photoreactor like Figure 1 As shown, the main components of the solid-phase photoreactor include connector 1, support frame 2, gas storage chamber 3, external rotary drive unit 4, light source 5, reaction flask 6, and magnetic stirrer 7.

[0040] Using this solid-phase photoreactor, the solid-phase carrier can be changed as needed, and the light source of different wavelengths can be changed as needed.

[0041] After the sample and solid support are filled into reaction flask 6, a magnetic pole is added. It is then directly connected to the corresponding interface of the external rotary drive unit 4 and fixed in place.

[0042] For air atmosphere response: Adjust the valve of connector 1 to allow the air storage chamber 3 to be directly connected to the atmosphere, keeping the system in a normal pressure air environment.

[0043] For reactions in special gas atmospheres: Follow these steps: (1) Close all passages of connector 1 and connect the gas bag pre-filled with the target gas (such as nitrogen, argon, etc.) to the designated interface of connector 1.

[0044] (2) Adjust connector 1 to connect the gas storage chamber 3 to the vacuum pump, and start the vacuum pump to perform vacuuming on the system.

[0045] (3) Turn off the vacuum pump, adjust connector 1 to connect the air bag with the gas storage chamber, and fill the system with the target gas.

[0046] (4) Repeat the “vacuuming-filling” process of steps (2) and (3) a total of three times to ensure that the air in the system is fully replaced and a pure and stable target gas reaction atmosphere is formed.

[0047] Turn on the light source 5, external rotation drive unit 4, and magnetic stirrer 7 to start the reaction.

[0048] When gas needs to be replenished during the experiment, close connector 1 to inflate the airbag, and then connect the airbag and open connector 1 after inflation.

[0049] Example 2: Hydroxylation of methyl 5-chloro-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 82.6% and a purity of 99.9%.

[0050] Example 3: Hydroxylation of methyl 4-chloro-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 82.8% and a purity of 99.9%.

[0051] Example 4: Hydroxylation of methyl 5-bromo-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 80.7% and a purity of 99.9%.

[0052] Example 5: Hydroxylation of methyl 6-fluoro-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 72.6% and a purity of 99.9%.

[0053] Example 6: Hydroxylation of methyl 4-methoxy-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 73.8% and a purity of 99.9%.

[0054] Example 7: Hydroxylation of methyl 5,6-dimethoxy-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 69.1% and a purity of 99.9%.

[0055] Example 8: Hydroxylation of methyl 1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the components were separated by column chromatography, with a yield of 99% and a purity of 99.9%.

[0056] Example 9: tert-butyl 5-chloro-1-indanone-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 6 h. After the reaction, the product was separated by column chromatography, with a yield of 70.5% and a purity of 99.9%.

[0057] Example 10: (3s,5s,7s)-adamantane-1-yl5-chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 6 h. After the reaction, the product was separated by column chromatography, with a yield of 75.9% and a purity of 99.9%.

[0058] Example 11: Methyl 1,2,3,4-tetrahydro-1-oxo-2-naphthylcarboxylate The substrate (0.2 mmol), diphenylamine (0.02 mmol, 0.1 eq), SiO2 (0.1 g), and 4A molecular sieve (0.2 g) were added to a 10 mL transparent reaction flask and mixed thoroughly. The reaction was carried out under 30 W white light in air at room temperature (10–30 °C) for 1 h. After the reaction, the product was separated by column chromatography, with a yield of 72.4% and a purity of 99.9%.

[0059] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for photo-induced α-hydroxylation solid-phase reaction of β-dicarbonyl compounds, characterized in that, The process includes the following steps: uniformly mixing the β-dicarbonyl compound reactant, catalyst, and solid support in a reactor, and carrying out a solid-phase reaction under oxygen-containing atmosphere, visible light irradiation, and room temperature conditions to obtain the α-hydroxy-β-dicarbonyl compound; the reaction equation is as follows; In the formula, R1 is a group at different substitution positions on the benzene ring, and the group is hydrogen, methyl, methoxy or halogen; n is 1 or 2; X is O or NH; R2 is methyl, ethyl, tert-butyl or adamantyl.

2. The method for photo-induced α-hydroxylation solid-phase reaction of β-dicarbonyl compounds according to claim 1, characterized in that, The catalyst is an inorganic base catalyst, a phase transfer catalyst, or an organic base catalyst; the inorganic base catalyst is potassium carbonate, potassium bicarbonate, or cesium carbonate; the phase transfer catalyst is tetrabutylammonium iodide, tetrabutylammonium chloride, or tetrabutylammonium bromide; the organic base catalyst is sodium methoxide, potassium tert-butoxide, n-butylamine, diethylamine, triethylamine, or an aromatic amine compound; the solid support is at least one of silica gel, titanium silicate molecular sieve, anhydrous magnesium sulfate, silicon carbide, carbon nitride, 4A molecular sieve, or nano-alumina.

3. The method for photo-induced α-hydroxylation solid-phase reaction of β-dicarbonyl compounds according to claim 2, characterized in that, The catalyst is aniline, diphenylamine, triphenylamine, bis(4-methoxyphenyl)amine, 4-methoxy-N-phenylaniline, 4-nitrodiphenylamine, N-phenyl-1-naphthylamine, or N,N-diphenyl-p-phenylenediamine; the solid support is a mixture of 4A molecular sieve and silica gel, and when using the mixture of 4A molecular sieve and silica gel, the mass ratio of 4A molecular sieve to silica gel is 1:1 to 4:1; the β-dicarbonyl compound substrate is a β-ketoester or β-diketone.

4. The method for photo-induced α-hydroxylation solid-phase reaction of β-dicarbonyl compounds according to claim 1, characterized in that, The wavelength of the light source is any wavelength within the range of 365–760 nm; the oxygen-containing atmosphere is air or oxygen atmosphere; and the reaction time is 1–12 h.

5. The method for photo-induced α-hydroxylation solid-phase reaction of β-dicarbonyl compounds according to claim 1, characterized in that, The amount of catalyst used is 0.1-1 equivalent of the molar amount of the β-dicarbonyl compound reactant.

6. The method for photo-induced α-hydroxylation solid-phase reaction of β-dicarbonyl compounds according to claim 4, characterized in that, The light source is a white light source.

7. A solid-phase photoreactor for photo-induced α-hydroxylation of β-dicarbonyl compounds, characterized in that, The method for implementing the photoinduced α-hydroxylation solid-phase reaction of β-dicarbonyl compound as described in any one of claims 1-6 includes a connector (1), a support frame (2), a gas storage chamber (3), an external rotation drive unit (4), a light source (5), a reaction flask (6), and a magnetic stirrer (7). The connector (1) is provided with three interfaces: an interface for connecting to an oxygen source, an interface for connecting to the gas storage chamber (3), and an interface for connecting to a vacuum pump. The gas storage chamber (3) is a sealed hollow structure with two interfaces: one is connected to the connector (1), and the other is connected to the external rotary drive unit (4). The support frame (2) is used to fix the gas storage chamber (3); The two ends of the external rotary drive unit (4) are respectively connected to the gas storage chamber (3) and the reaction bottle (6) interface, and the reaction bottle (6) can be driven to rotate mechanically by the motor contained in it; The reaction flask (6) is used to hold the magnetic stir bar, β-dicarbonyl compound reactants, catalyst and solid support; The magnetic stirrer (7) is placed at the bottom of the reaction flask (6); The light source (5) is placed above the reaction flask (6).

8. The solid-phase photoreactor according to claim 7, characterized in that, The oxygen source storage medium is a gas bag or a depressurized gas cylinder; it can be filled with different types of gas to flexibly adjust the reaction atmosphere according to experimental needs; the vacuum pump interface facilitates vacuuming and inert gas replacement in the solid phase photoreactor; valves are provided at the three interfaces of the connector (1).

9. The solid-phase photoreactor according to claim 7, characterized in that, The support frame (2) is equipped with a multi-directional adjustment mechanism, which can realize the precise positioning of the gas storage chamber (3) in the horizontal and vertical directions, making it easy to align the reaction bottle (6) with the light path; the reaction bottle (6) is made of high light transmittance glass or quartz material, and different volumes of bottles can be replaced according to the experimental scale to adapt to milligram to gram level solid phase reactions; the external rotary drive unit (4) drives it to rotate mechanically with the reaction bottle (6) through its internal motor, ensuring that the reaction bottle and its internal solid phase material can be uniformly illuminated by the light source (5); the magnetic stirrer (7) is used to drive the magnetic stir bar in the reaction bottle (6) to enhance the mixing of solid phase materials; the light source (5) is fixed on the platform of the magnetic stirrer (7), and the continuous lifting and lowering in the vertical direction is realized through the movable clamp, thereby precisely controlling the distance between the light source (5) and the reaction bottle (6) and adjusting the light intensity.

10. The solid-phase photoreactor according to claim 7, characterized in that, The reaction flask (6) is driven to rotate by the motor of the external rotary drive unit (4) on the one hand, and the reactants in the reaction flask (6) are magnetically stirred by the magnetic stirrer (7) on the other hand. The reactants in the reaction flask react through the dual action of rotation and stirring.

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