Method for regulating water-phase Mannich reaction activity and enantiomer selectivity based on Pickering emulsion interface

Abstract

The invention belongs to the technical field of catalysis, and particularly relates to a method for regulating and controlling water-phase Mannich reaction activity and enantiomer selectivity based on a Pickering emulsion interface. According to the method, a molecular catalyst is anchored on the surface of a solid emulsifier to form a stable Pickering emulsion system, and the activity and enantioselectivity of a water-phase Mannich catalytic reaction can be regulated and controlled by utilizing the interface characteristics of the Pickering emulsion system. According to the method, efficient utilization of the catalyst and precise regulation and control of the spatial configuration of the chiral product are achieved through the interfacial effect, the method is simple and easy to implement, the substrate application range is wide, and a new strategy is provided for green synthesis of chiral drugs and fine chemicals.

Description

Technical Field

[0001] The invention belongs to the technical field of catalysis, and particularly relates to a method for regulating the activity and enantiomeric selectivity of an aqueous phase Mannich reaction based on a Pickering emulsion interface. Background Art

[0002] The aqueous Mannich reaction, which introduces a chiral center via the formation of a C-N bond, is an important route for the synthesis of chiral drug intermediates such as β-aminoketones. This reaction system relies on water, a natural solvent. Its unique polar environment not only effectively stabilizes reaction intermediates but also, due to its zero-cost, non-toxic, and environmentally friendly properties, perfectly aligns with the core concepts of green chemistry and sustainable development. Recent research has further revealed that, in addition to being an environmentally friendly solvent, aqueous media can also promote reactions, accelerating them and improving selectivity. However, current aqueous catalytic systems have limitations. For one thing, hydrophobic substrates are difficult to dissolve in aqueous media, resulting in low mass transfer efficiency and hindering reaction progress. Furthermore, compared with established organic media reaction systems, aqueous catalytic systems that combine high catalytic activity with excellent enantioselectivity are relatively rare. Therefore, efficiently controlling the activity and enantioselectivity of aqueous catalytic reactions remains a challenging problem.

[0003] Pickering emulsions, oil-water systems stabilized by solid particles, have recently been used in heterogeneous catalysis. As a novel catalytic system, compared to traditional two-phase systems or surfactant emulsions, they not only create a large oil-water reaction interface, allowing for ample contact between substrate and catalyst, effectively addressing mass transfer efficiency issues, but also optimize the interfacial properties and catalytic activity of the emulsion by modifying the properties of the solid particles, such as the emulsion droplet size and emulsifier particle size. This precise control mechanism enables more effective control of the reaction process, significantly improving reaction efficiency and selectivity. Furthermore, the solid particles in the Pickering emulsion system serve as both emulsifier and catalyst, allowing for simple solid-liquid separation and subsequent recycling. The Pickering emulsion system offers a reaction interface and unique advantages unmatched by other aqueous catalytic systems, providing an ideal platform for aqueous Mannich reactions with high selectivity and stability. Its introduction into chiral catalysis promises to provide a novel solution for efficiently manipulating reaction activity and enantioselectivity, and an ideal reaction vehicle for the development of green chiral synthesis technologies. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides a method for regulating the activity and enantioselectivity of aqueous Mannich reactions based on the Pickering emulsion interface. This method forms a stable Pickering emulsion system by anchoring a chiral molecular catalyst to the surface of a solid emulsifier. The interfacial properties of this system can be used to regulate the activity and enantioselectivity of aqueous Mannich reactions. This method achieves efficient catalyst utilization and precise control of the stereoconfiguration of chiral products through interfacial effects. The method is simple and easy to implement, has a wide range of substrate applicability, and provides a new strategy for the green synthesis of chiral drugs and fine chemicals.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A method for regulating the activity and enantioselectivity of an aqueous phase Mannich reaction based on a Pickering emulsion interface comprises the following steps:

[0007] (1) dispersing a chiral molecular catalyst, a thiol functionalized material, and an initiator into a solvent, stirring, washing, and drying to obtain a solid emulsifier;

[0008] (2) dispersing the solid emulsifier in the oil phase, then adding the aqueous phase and emulsifying to obtain a Pickering emulsion; then adding an imine compound and a ketone compound to the Pickering emulsion to carry out a Mannich reaction to obtain a chiral β-aminoketone compound.

[0009] Furthermore, the chiral molecular catalyst in step (1) is cinchonidine; the thiol-functionalized material is thiol-functionalized silica with a particle size of 20 to 350 nm; and the initiator is azobisisobutyronitrile.

[0010] Through this technical solution, the chiral molecular catalyst cinchonidine is immobilized on the surface of the silica material through a click reaction between its double bond and the thiol group. The resulting solid particles serve as both an emulsifier and a chiral catalyst in the Pickering emulsion. After the reaction, the catalyst can be recovered and reused through simple solid-liquid separation. Furthermore, the physical presence of the solid emulsifier at the oil-water interface ensures the emulsion system remains stable for an extended period of time, providing a stable and unique chiral microenvironment for the reaction and facilitating its stable operation.

[0011] The particle size of the thiol-functionalized material is adjustable in the range of 20 to 350 nm. Therefore, the specific surface area of ​​the solid emulsifier can be adjusted by changing the particle size, thereby loading more catalyst and improving the Mannich catalytic reaction activity and enantiomeric selectivity.

[0012] Furthermore, the mass ratio of the chiral molecular catalyst, the thiol functionalized material and the initiator in step (1) is (1-1.1):2:(0.15-0.20).

[0013] Furthermore, in step (2), the oil phase is any one of toluene, mesitylene, p-xylene, n-octane, and n-octanol; the aqueous phase is a saturated sodium chloride solution; and the volume ratio of the oil phase to the aqueous phase is 2:1. In a preferred embodiment of the present invention, in step (2), the oil phase is toluene, mesitylene, or p-xylene, and the aqueous phase is a saturated sodium chloride solution.

[0014] Furthermore, the dosage ratio of the solid emulsifier to the oil phase in step (2) is (0.01-0.06) g:2 mL.

[0015] Furthermore, the emulsification conditions in step (2) are: emulsification speed 10000-15000 rpm, time 3-5 min.

[0016] The present invention constructs a stable Pickering emulsion system by fixing a chiral molecular catalyst on the surface of a solid emulsifier. The Pickering emulsion system has a reaction interface and unique advantages that are unmatched by other aqueous catalytic systems. It breaks the limitations of traditional reaction systems and utilizes the chiral microenvironment effect at the interface to achieve efficient regulation of the catalytic activity of the aqueous Mannich catalytic reaction and the enantioselectivity of the chiral product.

[0017] Furthermore, the Pickering emulsion is a water-in-oil type, and the diameter of the Pickering emulsion droplets is 200 to 2000 μm. The present invention regulates the Pickering emulsion droplet diameter by adjusting the amount of solid emulsifier used during the emulsification process, thereby optimizing the interfacial properties of the emulsion and precisely controlling the catalytic activity of the Mannich catalytic reaction and the enantioselectivity of the chiral product.

[0018] Furthermore, in step (2), the imine compound has a structure of Formula 1; the ketone compound has a structure of Formula 2; and the chiral β-aminoketone compound has a structure of Formula 3;

[0019]

[0020] Wherein R1 is selected from aryl, alkyl-substituted aryl, perfluoroalkyl-substituted aryl, alkoxy-substituted aryl, benzyloxy-substituted aryl, halogen-substituted aryl, and heterocyclic group; R2 and R3 are independently selected from alkyl or alkoxy groups.

[0021] Furthermore, the R1 is selected from one of the following substituents:

[0022]

[0023] Wherein, * represents a substitution site, X represents a halogen, a and b represent other attachment positions of the halogen, c and d represent other attachment positions of the trifluoromethyl group, and e and f represent other attachment positions of the methyl group. In a preferred embodiment of the present invention, R2 is a methyl group or a methoxy group, and R1 is selected from one of the following substituents:

[0024]

[0025] The Pickering emulsion system of the present invention can not only catalyze the Mannich reaction in different oil phase systems, but also has wide substrate applicability and flexibility in reaction conditions, thus providing more options and possibilities for the research and application of aqueous phase Mannich catalysis.

[0026] Furthermore, the temperature of the Mannich reaction in step (2) is 20°C.

[0027] The present invention has the following effects compared to the prior art:

[0028] 1. This invention proposes, for the first time, a method for regulating the activity and enantioselectivity of the aqueous Mannich reaction based on the Pickering emulsion interface. Compared with pure oil-phase and two-phase systems, the Pickering emulsion's large oil-water interface shortens the diffusion distance between the hydrophobic substrate and the catalyst, facilitating effective contact between the two. This overcomes the difficulties encountered in traditional aqueous systems, such as the difficulty in dissolving hydrophobic substrates and the low mass transfer efficiency. The unique oil-water interface microenvironment and the specific interactions between the catalyst and substrate at the interface effectively induce the formation of chiral products, resulting in products with high enantioselectivity.

[0029] 2. This invention anchors chiral catalyst molecules on the surface of a solid emulsifier to form a stable Pickering emulsion system. By varying the size or content of the solid emulsifier, the interfacial properties of the emulsion can be optimized, leading to precise control of the catalytic activity and enantioselectivity of the chiral product. Furthermore, the phase separation properties of the emulsion allow for convenient catalyst recovery and reuse through simple operations such as filtration, achieving resource recycling.

[0030] 3. The interfacial catalytic method of the present invention is based on a Pickering emulsion system. The system is stable, the conditions are mild, the substrates are widely applicable, and it can be carried out efficiently at room temperature and pressure, providing more options and possibilities for the research and application of aqueous Mannich catalysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Schematic diagram of the aqueous Mannich catalytic reaction based on the Pickering emulsion microinterface;

[0032] Figure 2 The graph is a comparison of the time-dependent curves of substrate conversion in the Mannich catalytic reaction in the Pickering emulsion system, the pure oil phase system, and the two-phase system;

[0033] Figure 3 Comparison of the enantiomeric excess of chiral products in the Mannich-catalyzed reaction in Pickering emulsion system, pure oil phase system, and two-phase system;

[0034] Figure 4 Microscope images and particle size statistics of different emulsion droplet sizes in the Pickering emulsion system;

[0035] Figure 5 A comparison of the catalytic activity and enantiomeric excess of the chiral product in the Mannich catalytic reaction at the microinterface of emulsion droplets of different sizes in the Pickering emulsion system;

[0036] Figure 6 Comparison of catalytic activity and enantiomeric excess of chiral products in the Mannich catalytic reaction at the microinterface of Pickering emulsion systems stabilized by different emulsifier particle sizes;

[0037] Figure 7 A comparison chart of the enantiomeric excess of chiral products in the Mannich-catalyzed reaction in Pickering emulsion systems with different oil phases;

[0038] Figure 8 Comparison chart of the yield and enantiomeric excess of different Mannich reaction substrates in the Pickering emulsion system. DETAILED DESCRIPTION

[0039] The technical solution of the present invention will be further described below in conjunction with specific embodiments. However, it should be understood by those skilled in the art that the following examples are only intended to illustrate the present invention and should not be construed as limiting the present invention. Specific conditions not specified in the examples are to be followed according to conventional conditions or the conditions recommended by the manufacturer. All reagents or instruments used, unless otherwise specified, are conventional products obtained from commercial channels.

[0040] The preparation method of mercapto-functionalized silica in the following examples and comparative examples is as follows:

[0041] 0.4 g of poloxamer F-127, 1.4 g of potassium sulfate, and 0.4 g of 1,3,5-mesitylene were weighed and dissolved in 24.0 mL of distilled water. The mixture was stirred vigorously at 13.5°C for 6 h. 0.6 g of 3-mercaptopropyltrimethoxysilane and 1.2 g of tetramethoxysilane were added to the mixture and stirred at 13.5°C for 24 h. The mixture was then transferred to a hydrothermal autoclave and placed in a 100°C oven for 24 h. After cooling to room temperature, the solid product was filtered, washed 2–3 times with distilled water and ethanol, and then dried under vacuum. The resulting solid material was refluxed in a concentrated hydrochloric acid-ethanol mixture (1 / 10, v / v). After 20 h, the mixture was filtered to obtain a solid product. The solid product was washed 2–3 times with distilled water and ethanol, and then dried under vacuum to obtain thiol-functionalized silica with a particle size of 20 nm.

[0042] (1) Effects of different systems on the activity and enantioselectivity of the Mannich reaction

[0043] In order to explore the effects of different systems on the Mannich reaction activity and enantioselectivity, the present invention carried out Example 1, Comparative Example 1-1 and Comparative Example 1-2 to demonstrate that the Pickering emulsion system of the present invention can effectively regulate the Mannich reaction activity and obtain products with high enantioselectivity.

[0044] Example 1

[0045] A method for regulating the activity and enantioselectivity of aqueous Mannich reaction based on Pickering emulsion interface. The schematic diagram of aqueous Mannich catalytic reaction is shown in Figure 1 As shown, the specific steps include:

[0046] (1) Under N2 atmosphere, cinchonidine (3.7 mmol) was added to 150 mL of ultra-dry acetonitrile containing the initiator azobisisobutyronitrile (AIBN, 1.02 mmol) and thiol-functionalized silica (particle size 20 nm, 2 g). The mixture was refluxed and stirred at 75°C for 48 h. After washing and drying, a solid emulsifier was obtained.

[0047] (2) The solid emulsifier (0.06 g) obtained in step (1) was ultrasonically dispersed in 2 mL of toluene, 1 mL of saturated brine was added, and the mixture was emulsified at a speed of 15,000 rpm for 3 min to form a stable Pickering emulsion; N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to the Pickering emulsion to carry out a Mannich catalytic reaction, and the reaction was carried out at 20° C. for 40 min; the conversion rate of the substrate N-(tert-butyloxycarbonyl)benzylideneamine and the enantioselectivity of the product (S)-3a (substance name: 1,1-Dimethylethyl N-[(1S)-2-acetyl-3-oxo-1-phenylbutyl]carbamate) were monitored by liquid chromatography.

[0048] The reaction formula of the Mannich catalytic reaction in this embodiment is as follows:

[0049]

[0050] Comparative Example 1-1

[0051] Comparative Example 1-1 uses a pure oil phase system to carry out the Mannich reaction, and the specific steps are as follows:

[0052] The solid emulsifier (0.06 g) obtained in step (1) of Example 1 was added to 3 mL of toluene, and then imine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to carry out a Mannich catalytic reaction at 20° C. for 40 min. The conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0053] Comparative Example 1-2

[0054] Comparative Example 1-2 uses a two-phase system to carry out the Mannich reaction, and the specific steps are as follows:

[0055] The solid emulsifier (0.06 g) obtained in step (1) of Example 1 was added to 3 mL of a toluene-water two-phase system (toluene / water = 2:1, v / v), and then N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to carry out a Mannich catalytic reaction. The reaction was carried out at 20° C. for 40 min; the conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0056] In the Mannich catalytic reaction of the above embodiment and comparative example, the substrate conversion rate changes with time as shown in the following figure: Figure 2 As shown, the enantiomeric excess comparison diagram of chiral products is as follows Figure 3 As shown. Figure 2 and Figure 3As can be seen, compared to the pure oil phase system of Comparative Example 1-1 (conversion rate of 83%, ee value of 26%) and the two-phase system of Comparative Example 1-2 (conversion rate of 91%, ee value of 60%), the conversion rate of the substrate in Example 1 of the present invention in the Pickering emulsion system reached 95%, and the ee value was as high as 94%. These results demonstrate that the Pickering emulsion-based catalytic system of the present invention can effectively induce the formation of chiral products and obtain products with high enantioselectivity.

[0057] (II) Effects of Pickering emulsions with different droplet sizes on the activity and enantioselectivity of the Mannich reaction

[0058] To investigate the effects of Pickering emulsion catalytic systems with different droplet sizes on the activity and enantiomeric selectivity of the Mannich reaction, Example 2 was conducted to demonstrate that the present invention can precisely regulate the catalytic activity of the Mannich reaction and the enantiomeric selectivity of the chiral product by adjusting the size of the emulsion droplets and optimizing the interfacial properties of the emulsion by varying the amount of solid emulsifier used.

[0059] Example 2

[0060] A method for regulating the activity and enantioselectivity of an aqueous phase Mannich reaction based on a Pickering emulsion interface specifically comprises the following steps:

[0061] (1) Preparation of solid emulsifier: same as in Example 1.

[0062] (2) 0.06 g, 0.04 g, 0.02 g and 0.01 g of solid emulsifier were ultrasonically dispersed in 2 mL of toluene, and 1 mL of saturated brine was added to each emulsifier. The mixture was emulsified at 15,000 rpm for 3 min to obtain Pickering emulsions with droplet sizes of 200 μm, 300 μm, 550 μm and 2,000 μm, respectively. N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to the Pickering emulsions for a Mannich catalytic reaction at 20 °C for 1 h. The conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0063] Microscope images and particle size statistics of different emulsion droplet sizes of the Pickering emulsion system are shown in Figure 2. Figure 4 As shown, a, b, c, and d correspond to 200 μm, 300 μm, 550 μm, and 2000 μm, respectively.

[0064] The comparison of the catalytic activity and enantiomeric excess of the chiral product in the above Mannich catalytic reaction at the microinterface of emulsion droplets of different sizes in the Pickering emulsion system is shown in the figure below. Figure 5 As shown. Figure 5 It can be seen that as the droplet size decreases, the enantiomeric selectivity increases. As the droplet size decreases from 2000 μm to 200 μm, the catalyst reaction activity remains at 95%, and the ee value gradually increases to 76%, 92%, 92% and 94%, respectively.

[0065] (III) Effects of solid emulsifiers with different particle sizes on the activity and enantioselectivity of the Mannich reaction

[0066] In order to explore the effects of Pickering emulsion catalytic systems with solid emulsifiers of different particle sizes on the activity and enantiomeric selectivity of the Mannich reaction, the present invention carried out Example 3 to demonstrate that the present invention adjusts the specific surface area by changing the particle size of the solid emulsifier, thereby loading more catalyst and improving the reaction activity and enantiomeric selectivity.

[0067] Example 3

[0068] A method for regulating the activity and enantioselectivity of an aqueous phase Mannich reaction based on a Pickering emulsion interface specifically comprises the following steps:

[0069] (1) Preparation of solid emulsifier: same as in Example 1.

[0070] (2) 0.06 g of solid emulsifiers of 60 nm, 100 nm, 250 nm and 350 nm were ultrasonically dispersed in 2 mL of toluene, and 1 mL of saturated saline was added. The mixture was emulsified at a speed of 15,000 rpm for 3 min to form stable Pickering emulsions. N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to the Pickering emulsions for a Mannich catalytic reaction at 20 °C for 1 h. The conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0071] The comparison of the catalytic activity and enantiomeric excess of the chiral product in the above Mannich catalytic reaction at the microinterface of Pickering emulsion system with different solid emulsifier particle sizes is shown in the figure below. Figure 6 As shown, from Figure 6 It can be seen that as the particle size of the solid emulsifier decreases from 350nm to 60nm, the substrate conversion rate increases from 94% to 96%, and the ee value gradually increases to 40%, 51%, 90%, and 94%, respectively. This indicates that smaller particle size solid emulsifiers can provide a larger specific surface area, load more catalyst, and thus improve reaction activity and enantioselectivity.

[0072] (IV) Universality of the Pickering emulsion system of the present invention in catalyzing the Mannich reaction

[0073] In order to demonstrate the universality of the Pickering emulsion system of the present invention in catalyzing the Mannich reaction, the present invention carried out Example 4, Comparative Example 4-1, Comparative Example 4-2 and Example 5, Comparative Example 5-1, Comparative Example 5-2, demonstrating that the Pickering emulsion system prepared by the present invention is not only adaptable to different oil phases, but also has a wide range of substrate applicability and flexibility in reaction conditions, providing more options and possibilities for the research and application of aqueous phase Mannich catalysis.

[0074] Example 4

[0075] A method for regulating the activity and enantioselectivity of an aqueous phase Mannich reaction based on a Pickering emulsion interface specifically comprises the following steps:

[0076] (1) Preparation of solid emulsifier: same as in Example 1.

[0077] (2) Preparation of Pickering emulsions with different oil phases: Solid emulsifier (0.06 g) was ultrasonically dispersed in 2 mL of n-octane, n-octanol, p-xylene, and mesitylene, respectively, and 1 mL of saturated saline was added to each of them. The mixture was emulsified at a speed of 15,000 rpm for 3 min to form a stable Pickering emulsion. N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to the Pickering emulsion for a Mannich catalytic reaction. The reaction was carried out at 20°C for 1 h. The conversion rate of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0078] Comparative Example 4-1

[0079] Comparative Example 4-1 uses a pure oil phase system to carry out the Mannich reaction, and the specific steps are as follows:

[0080] The solid emulsifier (0.06 g) obtained in step (1) of Example 1 was added to 3 mL of n-octane, n-octanol, p-xylene or mesitylene, respectively, and then N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were added to carry out a Mannich catalytic reaction at 20° C. for 1 h. The conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0081] Comparative Example 4-2

[0082] Comparative Example 4-2 uses a two-phase system to carry out the Mannich reaction, and the specific steps are as follows:

[0083] The solid emulsifier (0.06 g) obtained in step (1) of Example 1 was added to 3 mL of a two-phase system of n-octane-water (n-octane / water = 2:1, v / v), a two-phase system of n-octanol-water (n-octanol / water = 2:1, v / v), a two-phase system of p-xylene-water (p-xylene / water = 2:1, v / v), or a two-phase system of mesitylene-water (mesitylene / water = 2:1, v / v), respectively. N-(tert-butyloxycarbonyl)benzylideneamine (0.3 mmol) and 2,4-pentanedione (0.6 mmol) were then added to carry out a Mannich-catalyzed reaction. The reaction was carried out at 20° C. for 1 h. The conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0084] In the Mannich catalytic reaction of the above examples and comparative examples, the enantiomeric excess of the chiral product is compared as shown in the figure below: Figure 7 As shown. Figure 7 It can be seen that although the enantioselectivity is low when the polar solvent n-octanol is used as the oil phase, the enantioselectivity of the product in the Pickering emulsion system is significantly enhanced compared to the respective pure oil phase system and the two-phase system. The above catalytic results demonstrate that the Pickering emulsion system prepared by the present invention can be adapted to different oil phases, improving the activity of the corresponding Mannich catalytic reaction and the enantioselectivity of the chiral product.

[0085] Example 5

[0086] A method for regulating the activity and enantioselectivity of an aqueous phase Mannich reaction based on a Pickering emulsion interface specifically comprises the following steps:

[0087] (1) Preparation of solid emulsifier: same as in Example 1.

[0088] (2) Preparation of Pickering emulsions: 0.06 g and 0.01 g of the solid emulsifier obtained in step (1) were ultrasonically dispersed in 2 mL of toluene, 1 mL of saturated saline was added, and the mixture was emulsified at a speed of 15,000 rpm for 3 min to form stable Pickering emulsions with droplet sizes of 200 μm and 2,000 μm, respectively; different imine compounds (0.3 mmol) and different ketone compounds (0.6 mmol) were added to the Pickering emulsions for Mannich catalytic reaction, and the reaction was carried out at 20° C. for 1 h; the conversion rate of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0089] Comparative Example 5-1

[0090] Comparative Example 5-1 uses a pure oil phase system to carry out the Mannich reaction, and the specific steps are as follows:

[0091] The solid emulsifier (0.06 g) obtained in step (1) of Example 1 was added to 3 mL of toluene, and then different imine compounds (0.3 mmol) and different ketone compounds (0.6 mmol) were added to carry out a Mannich catalytic reaction at 20° C. for 1 h. The conversion rate of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0092] Comparative Example 5-2

[0093] Comparative Example 5-2 uses a two-phase system to carry out the Mannich reaction, and the specific steps are as follows:

[0094] The solid emulsifier (0.06 g) obtained in step (1) of Example 1 was added to 3 mL of a toluene-water two-phase system (toluene / water = 2:1, v / v), and then different imine compounds (0.3 mmol) and different ketone compounds (0.6 mmol) were added to carry out a Mannich catalytic reaction. The reaction was carried out at 20° C. for 1 h; the conversion of the substrate and the enantioselectivity of the product were monitored by liquid chromatography.

[0095] The comparison of the yield and enantiomeric excess of different substrates in the Mannich reaction in the Pickering emulsion catalytic system is shown in the figure. Figure 8 The results show that the Pickering emulsion system has a wide range of substrate applicability. Compared with the pure oil phase system and the two-phase system, the reaction activity and enantioselectivity of different substrates in the Pickering emulsion system are significantly enhanced. Moreover, as the droplet size decreases, the activity and ee value also increase.

[0096] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention and are not intended to limit the same. The basic principles and main features of the present invention have been described above using specific implementation schemes. Modifications or substitutions may be made based on the present invention, but such modifications or substitutions do not detract from the essence of the corresponding technical solutions from the scope of protection claimed by the present invention.

Claims

1. A method for regulating the activity and enantioselectivity of aqueous phase Mannich reaction based on Pickering emulsion interface, characterized in that: The steps include: (1) dispersing a chiral molecular catalyst, a thiol functionalized material, and an initiator into a solvent, stirring, washing, and drying to obtain a solid emulsifier; (2) dispersing the solid emulsifier in the oil phase, then adding the aqueous phase and emulsifying to obtain a Pickering emulsion; then adding an imine compound and a ketone compound to the Pickering emulsion to carry out a Mannich reaction to obtain a chiral β-aminoketone compound.

2. The method for regulating the water phase Mannich reaction activity and enantioselectivity based on the Pickering emulsion interface according to claim 1, characterized in that: In step (1), the chiral molecular catalyst is cinchonidine; the thiol-functionalized material is thiol-functionalized silica with a particle size of 20 to 350 nm; and the initiator is azobisisobutyronitrile.

3. The method for regulating the water phase Mannich reaction activity and enantioselectivity based on the Pickering emulsion interface according to claim 1, characterized in that: The mass ratio of the chiral molecular catalyst, the thiol functionalized material and the initiator in step (1) is (1-1.1):2:(0.15-0.20).

4. The method for regulating the water phase Mannich reaction activity and enantioselectivity based on the Pickering emulsion interface according to claim 1, characterized in that: The oil phase in step (2) is any one of toluene, mesitylene, p-xylene, n-octane, and n-octanol; the aqueous phase is a saturated sodium chloride solution; and the volume ratio of the oil phase to the aqueous phase is 2:

1.

5. The method for regulating the water phase Mannich reaction activity and enantioselectivity based on the Pickering emulsion interface according to claim 1, characterized in that: The dosage ratio of the solid emulsifier to the oil phase in step (2) is (0.01-0.06) g:2 mL.

6. The method for regulating the water phase Mannich reaction activity and enantioselectivity based on the Pickering emulsion interface according to claim 1, characterized in that: The emulsification conditions in step (2) are: emulsification speed 10000-15000 rpm, time 3-5 min.

7. The method for regulating aqueous phase Mannich reaction activity and enantioselectivity based on Pickering emulsion interface according to claim 1, characterized in that: The Pickering emulsion is of water-in-oil type; the diameter of the Pickering emulsion droplets is 200 to 2000 μm.

8. The method for regulating aqueous phase Mannich reaction activity and enantioselectivity based on Pickering emulsion interface according to claim 1, characterized in that: In step (2), the imine compound has a structure of Formula 1; the ketone compound has a structure of Formula 2; and the chiral β-aminoketone compound has a structure of Formula 3; Wherein R1 is selected from aryl, alkyl-substituted aryl, perfluoroalkyl-substituted aryl, alkoxy-substituted aryl, benzyloxy-substituted aryl, halogen-substituted aryl, and heterocyclic group; R2 and R3 are independently selected from alkyl or alkoxy groups.

9. The method for regulating the water phase Mannich reaction activity and enantioselectivity based on the Pickering emulsion interface according to claim 8, characterized in that: The R1 is selected from one of the following substituents: Wherein, * represents a substitution site, X represents a halogen, a and b represent other connection positions of the halogen, c and d represent other connection positions of the trifluoromethyl group, and e and f represent other connection positions of the methyl group.

10. The method for regulating aqueous phase Mannich reaction activity and enantioselectivity based on Pickering emulsion interface according to claim 1, characterized in that: The temperature of the Mannich reaction in step (2) is 20°C.

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