Preparation of sodium alginate poly(n-isopropylacrylamide) hydrogel catalyst and its application in chiral boron addition reaction

Abstract

The present application relates to a kind of sodium alginate poly (N-isopropyl acrylamide) hydrogel catalyst and its preparation and its application in catalytic chiral boron addition reaction, which is with α, β-unsaturated ketone compound, pinacol diboron as raw material, with sodium alginate poly (N-isopropyl acrylamide) hydrogel as catalyst, after adding chiral ligand, reaction at room temperature, after separation and purification, β-chiral boron compound is prepared. The catalyst raw material is widely used, low in cost, simple to prepare, can be recycled and reused, with the characteristics of environmental protection green, high yield and corresponding selectivity, excellent catalytic performance, has very high practical value in industry.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of catalyst materials, in particular to a sodium alginate poly (N-isopropyl acrylamide) hydrogel catalyst and its application in chiral boron addition reaction. BACKGROUND

[0002] Organoboron compounds have been widely used in the fields of synthetic chemistry, material science, life and health, etc. Therefore, the synthesis of organoboron compounds has always been a research hotspot. At present, the catalytic C-B bond formation reaction usually uses pinacol diboron (B2Pin2), pinacol borane (HBPin) and catechol borane (HBCat) as boron reagents. Compared with traditional boron reagents, the adducts of borane and strong Lewis bases such as amines, phosphines or N-heterocyclic carbines (collectively referred to as stable borane adducts) have the characteristics of easy synthesis, high stability and easy operation. As boron reagents, they have recently received more and more attention in the synthesis of organoboron compounds, and have been successfully used in the borohydration of alkenes (alkynes), C-H bond boronation, carbene insertion into B-H bond, boron radical tandem cyclization, substitution and other reactions, providing new ideas and methods for the synthesis of organoboron compounds.

[0003] The boron addition reaction plays a crucial role in synthesis, which refers to the dissociation of diborane into borane in an ether solution, and then the reaction of the B-H bond with the unsaturated bond of alkyne or alkene to form an organoboron compound. In the catalyst of the reaction, the catalysts used in chiral boron addition reaction mainly include supported copper. In the existing methods, high-activity monovalent copper is used in large quantities, which can easily cause metal residues in drug synthesis and requires reaction in an ultra-low temperature environment, which is harsh in reaction conditions and has high cost. Therefore, it is urgent to develop a simple and easy-to-operate, mild and low-cost, green and environmentally friendly catalyst. SUMMARY

[0004] The present application provides a sodium alginate poly (N-isopropyl acrylamide) hydrogel catalyst material, which aims to provide a green and efficient catalyst for chiral boron addition reaction. The existing catalysts have high cost and metal residue problems. Therefore, the present application uses sodium alginate as raw material, which greatly reduces the production cost, is green and easy to recycle without pollution. The material has relatively mild reaction conditions, is simple and easy to operate, and expands the application range and conditions of the material.

[0005] The technical solution of the present application to solve the above technical problems is as follows:

[0006] A preparation method of a sodium alginate poly (N-isopropyl acrylamide) hydrogel catalyst, comprising the following steps:

[0007] Step (1) NIPAA, MBAA, SA are added to the solution, after stirring, system one is obtained;

[0008] Step (2) system one obtained in step (1) is mixed with initiator, promoter and the like, and is stirred to react in a vacuum and an inert gas closed environment to obtain system two, and after drying, sodium alginate poly (N-isopropyl acrylamide) hydrogel (SAPH) is obtained;

[0009] Step (3) the SAPH hydrogel obtained in step (2) is placed in a copper salt solution and fully stirred, and after the SAPH hydrogel loaded with copper ions is dried, the catalyst can be obtained.

[0010] Further, the solution in step (1) is water, the amount is 20ml, the amount of SA is 8-12g / L, the mass ratio of NIPAA to SA is (3-25):2, and the mass ratio of MBAA to SA is (1-6):40.

[0011] Further, the initiator in step (2) is APS, the amount is 20mg, the promoter is TEMED, the amount is 6μl, and the reaction condition of step (2) is that the schlenk reaction tube is vacuumed and nitrogen is passed for 10 times, and stirred at room temperature for 10-12h.

[0012] Further, the concentration of Cu 2+ in the copper salt solution in step (3) is 1-1.5mol / L, and the copper salt is one of copper sulfate, copper nitrate and copper acetate; and the drying condition of step (3) is 50-60℃ oven, and the drying time is 10-12h.

[0013] The application also proposes to use the catalyst prepared in step (3) to catalyze chiral boron addition reaction, and the synthesis line of the application is as follows:

[0014] The synthesis steps are as follows:

[0015] Step 1, α, β-unsaturated ketone compound, bis(pinacolato)diboron, sodium alginate poly (N-isopropyl acrylamide) hydrogel catalyst and amine chiral ligand are added to a solvent and stirred at room temperature to react;

[0016] Step 2, the system obtained in step (1) is centrifuged and filtered, the liquid phase part is extracted, dried and rotary evaporated to obtain boride crude product;

[0017] Step 3, the boride crude product is mixed with an organic mixed solution at room temperature and stirred, and after reaction, the mixture is extracted, dried, rotary evaporated and column chromatographed to obtain β-chiral boron compound;

[0018] The structure of the α, β-unsaturated ketone compound is The β-chiral boron compound has a structure as shown in the following formula wherein R1 is phenyl, and R2 is p-phenyl, chlorophenyl, p-methoxyphenyl, p-bromophenyl, m-bromophenyl or naphthyl;

[0019] The amine chiral ligand is a chiral bipyridine ligand, and has a structure as shown in the following formula

[0020] Further, the volume ratio of toluene to water in the solvent in step 1 is (6-10):1.

[0021] Further, the molar ratio of the α, β-unsaturated ketone compound, pinacol diboron, sodium alginate poly(N-isopropyl acrylamide) hydrogel catalyst and amine chiral ligand in step 1 is 1:(1.2-1.7):(0.01-0.05):(0.01-0.05); and the reaction condition is stirring at room temperature for 6-14 hours.

[0022] Further, the extractant in step 2 is ethyl acetate, and the drying agent is anhydrous sodium sulfate.

[0023] Further, the organic mixed solution in step 3 comprises 244 mg of sodium borate tetrahydrate, 3.0 ml of THF and 2.0 ml of water; the reaction condition of step (3) is stirring at room temperature for 4-6 hours; the extractant of step (3) is ethyl acetate, and the drying agent of step (3) is anhydrous sodium sulfate.

[0024] Compared with the prior art, the catalyst prepared in the application has the following advantages in the synthesis of chiral boron compounds:

[0025] 1. The catalyst uses sodium alginate as a carrier, has excellent gel performance and hydrophilic performance, realizes good mass transfer of the substrate, a small amount of ligand (2% of the molar mass of the substrate) and a solvent on the surface of the catalyst, thereby improving the yield of the target product, the carrier material of the catalyst is widely available, low in cost and does not pollute the environment.

[0026] 2. The catalyst is prepared under mild conditions, reacts at room temperature with water as a solvent, is simple and easy to operate, generates no by-products and has a high yield.

[0027] 3. The catalyst is convenient to recover after the reaction and can be reused, thereby greatly reducing the industrial production cost.

[0028] 5. The catalyst has excellent catalytic effect, can effectively improve the yield of the reaction and reduce the generation of by-products.

[0029] 6. The method has wide applicability to substrates and can be successfully applied to chiral conjugate addition reactions of different types of unsaturated compounds. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 The Fourier infrared spectra of SAPH before and after loading copper in Example 1.

[0031] Figure 2 The contact angle measurement chart of SAPH in Example 1. DETAILED DESCRIPTION

[0032] Example 1

[0033] 0.2 g of sodium alginate (SA) was added to 20 ml of water to obtain a sodium alginate (SA) solution. 1.5 g of N-isopropyl acrylamide (NIPAA) and 20.4 mg of N,N-methylene bisacrylamide (MBAA) were added to the sodium alginate (SA) solution, and the mixture was stirred at room temperature to obtain system one. System one, 20 mg of ammonium persulfate (APS), and 6 μl of tetramethyl ethylenediamine (TEMED) were added to a schlenk reaction tube, and the mixture was vacuumed and purged with nitrogen for 10 times, and then stirred at room temperature for 12 h to obtain system two. System two was dried in an oven at 60°C for 12 h to obtain sodium alginate poly(N-isopropyl acrylamide) hydrogel (SAPH).

[0034] A 1 mol / L copper sulfate solution was prepared, and the SAPH obtained in the above step was placed in the 1 mol / L copper sulfate solution and stirred for 12 h to load copper ions. The SAPH loaded with copper ions was dried in an oven at 60°C for 12 h to obtain SAPH@Cu catalyst.

[0035] Figure 1 The Fourier infrared spectra of SAPH before and after loading copper, and the infrared spectra in the figure prove that the sodium alginate poly(N-isopropyl acrylamide) hydrogel (SAPH) has characteristic peaks of sodium alginate and N-isopropyl acrylamide, and the polymer structure is correct. The catalyst obtained after loading copper still retains the characteristic peaks of the polymer, and the loading of copper ions does not destroy the polymer structure. According to the analysis of the infrared spectra, characteristic peaks appear at 3118 cm -1 and 1688 cm -1 , which prove the characteristic peaks of the amide bond in N-isopropyl acrylamide; a characteristic peak appears at 600 cm -1 , which is the coordination characteristic peak of copper ions, and copper is successfully loaded.

[0036] Figure 2 The contact angle measurement chart of SAPH, which proves that the catalyst has good hydrophilic performance.

[0037] In the present catalyst, sodium alginate having good hydrophilic property is used, and a uniform viscous colloid can be first prepared, which has softness and uniformity, and can be made into strong fibers (alginic acid fibers) or films, and has a crack prevention effect. The hydrogel film prepared by the chitosan in the prior art is difficult to shape. Therefore, the catalyst based on sodium alginate as a carrier has excellent gel performance and hydrophilic performance, can promote the mass transfer in the water medium, and can realize good mass transfer of the substrate and the solvent on the surface of the catalyst, thereby improving the yield of the target product.

[0038] Example 2

[0039] The catalyst in Example 1 was taken, and (E)-3-(4-p-methoxyphenyl)-1-2-alken-1-one 0.2 mmol, pinacol diboronic acid 0.24 mmol, catalyst SAPH@Cu 0.002 mmol, amine chiral ligand 0.002 mol were added into a solvent, and stirred at room temperature for 12 h. The volume ratio of the solvent was 9:1 (toluene 1.8 mL, water 0.2 mL). The obtained system was centrifuged and filtered, and the liquid phase was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and rotary evaporated to obtain boronate crude product. The above boronate crude product, 244 mg of sodium borate tetrahydrate, 3.0 ml of THF, and 2.0 ml of water were mixed and stirred at room temperature for 6 h. Then extracted with ethyl acetate,

[0040] dried with anhydrous sodium sulfate, rotary evaporated, and column chromatography to obtain a β-chiral hydroxyl compound. After the precipitate was washed and dried with distilled water, the recovered catalyst material was obtained, and can be used for the next cycle.

[0041]

[0042] In the present example, the amine chiral ligand is a chiral bipyridine ligand, and the structural formula is as follows,

[0043]

[0044] The results of the present example show that the yield and enantiomeric selectivity of the target product are 96% and 95%, respectively, when the catalyst material is used in the reaction.

[0045] Example 3

[0046] The catalyst in Example 1 was taken, (E)-3-(4-p-bromo)-1-2- en-1-one 0.2 mmol, pinacol diboronic acid 0.24 mmol, catalyst 0.002 mol, amine chiral ligand 0.002 mol were added into solvent, stirred at room temperature for 12 h, the solvent was a mixture of toluene and water with volume ratio of 9:1 (toluene 1.8 mL, water 0.2 mL). The resulting system was centrifuged, filtered, the liquid phase was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and rotary evaporated to obtain boronate crude product. The above boronate crude product, 244 mg of sodium borate tetrahydrate, 3.0 ml of THF, 2.0 ml of water were mixed and stirred at room temperature for 6 h. Then extracted with ethyl acetate, dried with anhydrous sodium sulfate, rotary evaporated, and column chromatographed to obtain β-chiral hydroxyl compound. After the precipitate was washed and dried with distilled water, the recovered catalyst material was obtained and could be used for the next cycle.

[0047]

[0048] The amine chiral ligand in this example was a chiral bipyridine ligand, and the structure was as follows,

[0049]

[0050] The results of this example showed that the catalyst material was used in the reaction, and the yield and enantiomeric selectivity of the target product were 92% and 90%, respectively.

[0051] Example 4

[0052] The catalyst in Example 1 was taken, (E)-3-(4-p-bromo)-1-2- en-1-one 0.2 mmol, pinacol diboronic acid 0.24 mmol, catalyst 0.002 mol, amine chiral ligand 0.002 mol were added into solvent, stirred at room temperature for 12 h, the solvent was a mixture of toluene and water with volume ratio of 9:1 (toluene 1.8 mL, water 0.2 mL). The resulting system was centrifuged, filtered, the liquid phase was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and rotary evaporated to obtain boronate crude product.

[0053] The above boronate crude product, 244 mg of sodium borate tetrahydrate, 3.0 ml of THF, 2.0 ml of water were mixed and stirred at room temperature for 6 h. Then extracted with ethyl acetate, dried with anhydrous sodium sulfate, rotary evaporated, and column chromatographed to obtain β-chiral hydroxyl compound. After the precipitate was washed and dried with distilled water, the recovered catalyst material was obtained and could be used for the next cycle.

[0054]

[0055] The amine chiral ligand in this example was a chiral bipyridine ligand, and the structure was as follows,

[0056]

[0057] The results of this example show that the catalytic material used in the reaction has a target product yield and enantiomeric selectivity value of 91%, 88%, respectively.

[0058] Example 5

[0059] The catalyst after reaction in Example 2 was washed with hot water and dried in an oven at 40°C for 2h to obtain the recovered catalyst. According to the reaction steps of Example 2, (E)-3-(4-p-methoxyphenyl)-1-2- en-1-one 0.2mmol, pinacol diboronic acid 0.24mmol, recovered catalyst 0.002mol, chiral amine ligand 0.002mol were added to the solvent (toluene 1.8mL, water 0.2mL) and stirred at room temperature for 12h. The resulting system was centrifuged, filtered, and the liquid phase was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and rotary evaporated to obtain the crude chiral boronide product. The above boronide, 244mg sodium borate tetrahydrate, 3.0ml THF, 2.0ml water were mixed and stirred at room temperature for 6h. Subsequently, extraction, drying, rotary evaporation, and column chromatography were performed to obtain the β-chiral hydroxyl compound.

[0060] The above steps were repeated 5 times, and the results showed that, with (E)-3-(4-p-methoxyphenyl)-1-2-en-1-one as the reaction substrate, the catalytic effect of the catalyst after being used for the fifth time was still good, and the yield and enantiomeric selectivity value of the target product were 92%, 90%, respectively, which could still be maintained above 90%, indicating that the catalyst had good reusability.

Claims

1. Use of a sodium alginate poly(N-isopropylacrylamide) hydrogel catalyst in the preparation of N - chiral boron compounds, characterized in that β - chiral boron compounds, characterized in that The synthesis comprises the following steps: Step (1) α, β-unsaturated ketone compound, bis-pinacol borate, sodium alginate poly N - isopropyl acrylamide) hydrogel catalyst, amine chiral ligand into the solvent, stirring at room temperature reaction; Step (2) centrifuging, filtering the system obtained in step (1), drying and rotary evaporating the liquid phase after extraction to obtain boride crude product; Step (3) The boron compound crude product in step (2) is mixed with the organic mixed solution at room temperature and stirred. After reaction, the mixture is extracted, dried, rotary evaporated, and column chromatographed to obtain β - chiral boron compounds; The α,β-unsaturated ketone compound has a structure formula , and the β chiral boron compound has a structure formula including ; The amine chiral ligand is a chiral bipyridine ligand, and the structural formula is ; The volume ratio of toluene to water in step (1) is 9:1; The amount-of-substance ratio of the α,β-unsaturated ketone compound, pinacol diborane, sodium alginate poly N - isopropyl acrylamide) hydrogel catalyst, amine chiral ligand was 1:1.2:0.02:0.02; the reaction condition was stirring at room temperature for 6-14 h.

2. Use according to claim 1, characterized in that, Said sodium alginate poly N The preparation steps of the catalyst of isopropyl acrylamide hydrogel are as follows, Step (S1 ) adding N - isopropyl acrylamide NIPAA, N,N'-methylene bisacrylamide MBAA, sodium alginate SA are added to the solution, after stirring a system one is obtained; Step (S2) mixing system one obtained in step (S1) with initiator, accelerator, stirring in inert gas in a closed container to obtain system two, drying to obtain sodium alginate poly (acrylamide) hydrogel SAPH N - isopropyl acrylamide) hydrogel SAPH; Step (S3) placing the SAPH hydrogel obtained in step (S2) in a copper salt solution and fully stirring, drying the SAPH hydrogel loaded with copper ions to obtain a catalyst.

3. Use according to claim 2, characterized in that, The solution in step (S1) is water, the amount of which is 20 ml, the amount of SA is 8-12 g / L, the mass ratio of NIPAA to SA is (3-25):2, and the mass ratio of MBAA to SA is (1-6):

40.

4. Use according to claim 2, characterized in that, The initiator in step (S2) is ammonium persulfate APS, the amount of which is 1-25 g / L, the promoter is tetramethyl ethylenediamine TEMED, the amount of which is 0.3 ml / L, and the reaction condition of step (2) is 10 times of vacuum pumping and nitrogen injection in a schlenk reaction tube, stirring at room temperature for 10-12 h.

5. The use according to claim 2, characterized in that, In step (S3), the copper salt solution contains Cu 2+ The concentration is 1-1.5 mol / L, and the copper salt is selected from copper sulfate, copper nitrate, and copper acetate; the drying conditions in step (3) are 50-60 ℃ oven, drying for 10-12 h.

6. Use according to claim 1, characterized in that, The extracting agent in step (2) is ethyl acetate, and the drying agent is anhydrous sodium sulfate.

7. Use according to claim 1, characterized in that, The organic mixed solution in step (3) comprises sodium borate tetrahydrate, THF and distilled water, wherein the amount of sodium borate tetrahydrate is 244 mg, the amount of THF is 3 mL, and the amount of water is 2 mL; the reaction condition of step (3) is stirring at room temperature for 4-6 h; the extracting agent of step (3) is ethyl acetate, and the drying agent of step (3) is anhydrous sodium sulfate.

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