Preparation and application of a chiral cyclohexanediamine-supported polyisonitrile catalyst

Abstract

The invention discloses a preparation method and application of a chiral cyclohexanediamine-supported polyisonitrile catalyst, wherein the catalyst is a helical polyisonitrile modified with chiral cyclohexanediamine; the preparation method comprises the following steps: using cyclohexanediamine as a starting material to synthesize an isonitrile monomer containing chiral cyclohexanediamine in the side chain, and then polymerizing it into a chiral cyclohexanediamine-supported catalyst poly-2 m The catalyst catalyzed the asymmetric Michael addition reaction in the presence of methanol and benzoic acid, with the enantiomeric excess (ee) and diastereomeric ratio (dr) of the product reaching 97% and 81 / 19, respectively. The cyclohexanediamine-supported catalyst showed high catalytic activity and stereoselectivity, providing ideas for the subsequent exploration of other reaction types.

Description

Technical Field

[0001] The present invention relates to the technical field of supported catalyst catalytic reaction, in particular to the preparation and application of a chiral cyclohexanediamine supported polyisonitrile catalyst. Background Art

[0002] Optically pure chiral cyclohexanediamine is an important pharmaceutical intermediate with extensive applications in medicine and asymmetric catalysis. Chiral cyclohexanediamine offers excellent catalytic activity, high enantioselectivity, and low raw material costs, making it widely used in asymmetric hydrogenation, Aldol reactions, Michael reactions, DA reactions, and Aza-Henry reactions. However, chiral cyclohexanediamine suffers from shortcomings such as high solubility and difficulty in separation and recovery. Researchers have addressed this issue by immobilizing chiral cyclohexanediamine on organic polymer supports or copolymerizing it with other molecules. Polyisocyanides have a helical structure, and chiral groups on their side chains can interact synergistically with the main chain, providing a more chiral microenvironment. This allows polyisocyanides to serve as supports for many small molecule catalysts. This novel supported catalyst with multiple catalytic sites can enhance the stereoselectivity of Michael reactions and has become a hot topic of research.

[0003] Zlotin et al. [Mendeleev Commun., 2017, 27:473-475] prepared a cyclohexanediamine-based ionic liquid to catalyze the Michael addition reaction between aldehydes and maleimides, achieving an ee value of up to 84%. Durmaz et al. [Molecular Catalysis, 2022, 526:112383] covalently grafted a silane compound containing cyclohexanediamine and thiourea groups onto a graphene oxide backbone via a silane coupling reaction, preparing two bifunctional graphene oxide-supported catalysts. They catalyzed the asymmetric Michael addition reaction of α,α-disubstituted aldehydes with maleimide derivatives in dichloromethane at room temperature, achieving an ee value of up to 95%. Pang et al. [Chemical Engineering Science, 2022, 260: 117933] used a pre-prepared sulfonic covalent organic framework and chiral 1,2-diaminocyclohexane to prepare a sulfonated chiral covalent organic framework (SDA-CCOF) by N-sulfonic sulfonylation, which was used for the asymmetric Michael addition reaction of β-nitrostyrene and acetone with an enantioselectivity of 90%.

[0004] Therefore, researchers in this field are committed to developing a cyclohexanediamine-based supported catalyst that can be recycled and has high catalytic activity, and to providing an asymmetric Michael reaction catalyst and its preparation method and application. Summary of the Invention

[0005] In view of the shortcomings of existing chiral cyclohexanediamine, such as good solubility but difficulty in separation and recovery, the present invention provides a cyclohexanediamine-supported catalyst that can be recycled without affecting the catalytic activity and has high catalytic activity, thereby filling the gap in existing catalyst types.

[0006] The first aspect of the present invention provides a method for preparing a chiral cyclohexanediamine-supported polyisonitrile catalyst.

[0007] The method specifically comprises the following steps:

[0008] Step 1: Add chiral cyclohexanediamine isonitrile monomer and palladium initiator into a 10 mL polymerization bottle;

[0009] Step 2: Under anhydrous and oxygen-free conditions, the nitrogen atmosphere was replaced three times, and dry tetrahydrofuran was added under N2 flow;

[0010] Step 3, react at 50-60°C for 10-24h, and add methanol to terminate the reaction;

[0011] Step 4: Add a large amount of ether to precipitate a solid;

[0012] Step 5: Centrifuge the solid and vacuum dry it to constant weight. The resulting product is poly-2 m s;

[0013] Furthermore, the structural formula of the palladium initiator is:

[0014] Further, the synthetic route is:

[0015]

[0016] The chiral cyclohexanediamine isonitrile monomer can be replaced by its derivatives, not limited to N,N-dimethyl, and can be a primary amine, a secondary amine or a tertiary amine;

[0017] The second aspect of the present invention provides an application of a chiral cyclohexanediamine-supported polyisonitrile catalyst to an asymmetric Michael addition reaction in different solvents and different co-catalysts. Taking methanol and benzoic acid as an example, the specific application process is as follows: a certain amount of supported catalyst, a certain amount of nitroolefin, and cyclohexanone are added to a reaction flask, a certain amount of methanol is added, and after stirring at room temperature for a certain time, a certain amount of co-catalyst benzoic acid is added, and the reaction is carried out at 25°C for a certain time. Ether is added, the reaction is centrifuged, dried, and the catalyst is recovered; the filtrate is concentrated and separated by column chromatography to obtain the corresponding asymmetric Michael addition product; the above reaction formula is:

[0018]

[0019] Furthermore, in the reaction formula, R is independently phenyl, substituted phenyl, aryl, alkyl, or halogen;

[0020] Furthermore, the solvent is one of chloroform, 1,2-dichloroethane, anhydrous ethanol, dichloromethane, toluene, methanol, saturated sodium chloride, water, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide / water, and acetonitrile;

[0021] Furthermore, the catalyst is one of benzoic acid, p-toluenesulfonic acid, and triethylamine;

[0022] Using the above scheme, the preparation and application of a chiral cyclohexanediamine-supported polyisonitrile catalyst disclosed in the present invention have the following advantages:

[0023] (1) The preparation and application of a chiral cyclohexanediamine-supported polyisocyanide catalyst of the present invention. The cyclohexanediamine-supported catalyst exhibits high catalytic activity and stereoselectivity. Under the condition of reasonable solvent and co-catalyst, the catalytic activity of the catalyst can be continuously optimized. The catalyst also has a wide range of applications and can catalyze asymmetric Michael addition reactions of various substrates.

[0024] (2) The preparation and application of a chiral cyclohexanediamine-supported polyisocyanide catalyst of the present invention are easy to recover, and after multiple recovery and recycling of the supported catalyst, the activity of the catalytic reaction and the stereoselectivity of the product are maintained at a good level;

[0025] In summary, the present invention discloses a preparation and application of a chiral cyclohexanediamine-supported polyisonitrile catalyst. The cyclohexanediamine-supported catalyst exhibits high catalytic activity and stereoselectivity. Under reasonable conditions of solvent and co-catalyst, the catalytic activity of the catalyst can be continuously optimized and has a wide range of applications. At the same time, the catalyst is easy to recover, and after multiple recycling, the activity of the catalytic reaction and the stereoselectivity of the product are maintained at a good level.

[0026] The concept, specific technical solutions and technical effects of the present invention will be further described below in conjunction with specific implementation methods to fully understand the purpose, characteristics and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 1. A step diagram of the preparation method of the chiral cyclohexanediamine-supported polyisonitrile catalyst of the present invention;

[0028] Figure 2 Compound 1b of the present invention 1 HNMR (400 MHz);

[0029] Figure 3 is compound 1c of the present invention 1HNMR (400 MHz);

[0030] Figure 4 Compound 1d of the present invention 1 HNMR (400 MHz);

[0031] Figure 5 Compound 1e of the present invention 1 HNMR (400 MHz);

[0032] Figure 6 Compound 2 of the present invention 1 HNMR (400 MHz);

[0033] Figure 7 Compound 2 of the present invention 13 CNMR (400MHz);

[0034] Figure 8 The high performance liquid chromatogram of the racemate 2-(2-nitro-1-phenylethyl)cyclohexan-1-one of the present invention (Chiralpak AS-H; isopropanol:n-hexane = 10 / 90 (v / v); flow rate 1.0 mL / min; 254 nm; 25° C.) is shown;

[0035] Figure 9 The figure is a high performance liquid chromatogram of the chiral (S)-2-((R)-2-nitro-1-phenylethyl)cyclohexan-1-one of the present invention (Chiralpak AS-H; isopropanol:n-hexane = 10 / 90 (v / v); flow rate 1.0 mL / min; 254 nm; 25°C). DETAILED DESCRIPTION

[0036] The following describes several preferred embodiments of the present invention to make its technical content clearer and easier to understand. The present invention can be embodied in many different forms of embodiments, which are for illustrative purposes only and the scope of protection of the present invention is not limited to the embodiments mentioned herein.

[0037] If there are experimental methods without specific conditions, they are usually implemented according to conventional conditions, such as those in the relevant instructions or manuals.

[0038] Examples 1 to 6 are six steps in the process of synthesizing (1R, 2R)-cyclohexanediamine isonitrile monomer;

[0039] The specific reaction formula of the synthesis process is:

[0040]

[0041] Example 1. Synthesis of Compound 1a

[0042] Add L-(+)-tartaric acid (15.0 g, 0.10 mol) to a 100 mL clean, dry three-necked flask, then add 20 mL of deionized water and stir to dissolve. Heat to 70°C and slowly add cyclohexanediamine (17.3 g, 0.15 mol), controlling the temperature below 90°C. Continue stirring for 10 min, slowly add glacial acetic acid (14 mL) dropwise, cool to 5°C in an ice-water bath, and react for 5 h. Filter, wash the filter cake with a small amount of methanol, and recrystallize the filter cake from water to obtain 15.3 g of a white solid with a yield of 58%. 1 HNMR (D2O, 400MHz), δ: 4.27 (s, 2H, CH); 3.34~3.26 (m, 2H, CH2); 2.12~2.08 (d, J=16.1 Hz,2H,CH2); 1.81~1.71(m,2H,CH2); 1.51~1.42(m,2H,CH2); 1.35~1.27(m,2H,CH2);

[0043] Example 2: Synthesis of Compound 1b

[0044] Under nitrogen protection, compound 1a (15.0 g, 0.057 mol) and 250 mL of 8 M sodium hydroxide aqueous solution were added to a 500 mL two-necked flask and stirred for 30 min. Dichloromethane was added for extraction (3 × 30). The mixture was allowed to stand, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.4 g of the product with a yield of 67.6%. 1 HNMR (CDCl3, 400MHz), δ: 2.23~2.17(m,2H,CH); 1.81~1.75(m,2H,CH2); 1.65~1.58(m,2H,CH2); 1.27~1.18(m,2H,CH2); 1.10~0.97(m,2H,CH2);

[0045] Example 3: Synthesis of Compound 1c

[0046] Weigh p-toluenesulfonic acid (12.5 g, 0.07 mol) into a 1000 mL three-necked flask, add 500 mL of xylene, then weigh compound 1b (8.0 g, 0.07 mol) and phthalic anhydride (10.4 g, 0.07 mol) and add them to the reaction flask. Heat to 160°C for 6 h, cool to room temperature, filter, wash the solid three times with n-hexane, then transfer it to a round-bottom flask, pour the resulting solid into 20 mL of saturated sodium bicarbonate solution and 100 mL of dichloromethane, stir at room temperature for 15 h, separate the organic phase, extract the aqueous phase with dichloromethane (3 × 30 mL), combine the organic phases, add anhydrous sodium sulfate to dry, filter, and concentrate to give 13.0 g of a white solid (yield 76%); mp 250-251°C; 1HNMR (CDCl3, 400MHz), δ: 7.85~7.81(m,2H,ArH); 7.71~7.68(m,2H,ArH); 3.83~3.76(m,1H,CH); 3.44~3.38(m,1H,CH); 2.23~2.14(m,1H,CH); 2.08~2.08(m,1H,NH); 1.86~1.75(m,3H,NH,CH2); 1.48~1.31(m,2H,CH); 1.25~1.16(m,3H,CH);

[0047] Example 4: Synthesis of Compound 1d

[0048] Mono-protected (1R,1R)-cyclohexanediamine compound 1c (5.0 g, 0.02 mol) was slowly added to 4.2 mL of 37% formaldehyde solution and 9.9 mL of formic acid solution in a 100 mL sealed tube. The mixture was heated to 70°C and refluxed overnight. The reaction was monitored by TLC. After the reaction was completed, 50 mL of dichloromethane was added and the pH was adjusted to 9 with 4 M sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane (30 mL × 3), dried, and concentrated to dryness under reduced pressure to obtain 4.9 g of light yellow solid compound 1d in a 90% yield; mp 116-118°C. 1 H NMR (DMSO-d6, 400MHz), δ: 7.83 (s, 4H, ArH); 4.05~3.97 (m, 1H, CH); 3.19~3.13 (m,1H,CH); 2.05(s,6H,CH3); 1.89~1.72(m,4H,CH2); 1.30~1.12(s,4H,CH2);

[0049] Example 5: Synthesis of Compound 1e

[0050] Compound 1d (4.0 g, 14.7 mmol) was dissolved in 100 mL of ethanol, and 4.0 mL of hydrazine hydrate (36.2 mmol) was added. The mixture was heated to 70°C and stirred under reflux for 1 h. A large amount of white solid precipitated. The mixture was cooled to room temperature and filtered with diethyl ether. The filtrate was collected. The filtrate was rotary dried and then dissolved in diethyl ether and filtered until no precipitate was present. Finally, 1.5 g of a light yellow liquid 1e was obtained with a yield of 74%. 1 HNMR (DMSO-d6, 400MHz), δ: 3.25~3.19(2H,NH2); 2.17(s,6H,CH3); 2.00~1.55(m,6H,CH2); 1.17~0.98(m,4H,CH2);

[0051] Example 6, Synthesis of Compound 2

[0052] To a 100 mL three-necked flask, 2.0 g (0.006 mol) of pentafluorophenyl-4-isocyanatobenzoate, 0.9 g (0.006 mol) of compound 1e, 25 mL of tetrahydrofuran, and 0.4 mL of triethylamine were added. The temperature was raised to 55°C and the reaction was allowed to react for 20 h. The reaction was confirmed by TLC and concentrated to give an orange viscous oily crude product. Column chromatography with an eluent (V (dichloromethane):V (methanol) = 5:1) afforded 1.2 g of compound 2 as a light yellow oil, with a yield of 74%. 1 H 3 .59-3.47(m,1H,CH); 2.32(s,6H,CH3); 1.95~1.88(m,2H,CH2); 1.76~1.72(m,1H,CH); 1.30~1.18(m,4H,CH2); 0.88~0.82(m,1H,CH). 13 C NMR (DMSO-d6, 100MHz), δ: 165.96, 164.41, 136.24, 129.29, 126.77, 50.16, 33.30, 25.17, 25.11, 22.99;

[0053] Example 7: Typical polymer poly-2 m s polymerization process, with poly-2 200 For example

[0054] Weigh the isonitrile compound 2 (108.5 mg, 0.4 mmol) in a 10 mL polymerization bottle, replace the atmosphere with nitrogen, weigh the palladium initiator (1.0 mg, 2.0 μmol) and dissolve it in 2.0 mL of dry THF, then add it to the polymerization bottle; heat to 55 ° C, stir and react for 23 hours, cool to room temperature, add ether, centrifuge, pour out the supernatant, dissolve the precipitate with a small amount of chloroform, add ether, precipitate the solid, centrifuge, repeat 3 times, and dry the separated solid in vacuum at room temperature for 12 hours to obtain a light yellow solid polymer poly-2. 200 (76.1mg, 70.1%); FT-IR (KBr, 25℃, cm -1 ):2935,2129,1747,1510;

[0055] Example 8, poly-2 m Catalytic asymmetric Michael reaction

[0056] In a 10 mL single-necked flask, add 20% mol of the catalyst (calculated based on the polymer repeating unit) of the substrate nitroolefin, 4 equivalents of cyclohexanone, and 0.5 mL of the reaction solvent. Stir the reaction at the set temperature. After the reaction is completed, track the reaction by thin-layer chromatography. Add a large amount of ether to precipitate the catalyst, centrifuge, concentrate the supernatant, and separate it with ethyl acetate and petroleum ether (v / v = 1 / 4) to obtain the corresponding Michael addition reaction product.

[0057] For the screening of solvents, the asymmetric Michael addition reaction of trans-β-nitrostyrene and cyclohexanone was used as a model reaction (the reaction formula is shown below) to evaluate the catalyst poly-2 200 The catalytic performance of the catalyst was tested at room temperature, and 11 solvents including chloroform, 1,2-dichloroethane, ethanol, dichloromethane, toluene, methanol, saturated sodium chloride solution, water, tetrahydrofuran, N,N-dimethylamide, and acetonitrile were tried. As shown in Table 1, when dichloromethane was used as the solvent, the catalytic activity and enantioselectivity were the best, with an ee value of up to 78%; when chloroform was used as the solvent, the catalytic activity and enantioselectivity were second best, with an ee value of 76%.

[0058]

[0059] Catalyzed Michael addition reaction of cyclohexanone and β-nitrostyrene

[0060] Table 1 Effects of different solvents on Michael addition reactions catalyzed by supported catalysts

[0061]

[0062] In the screening of additives, the catalyst exhibited good enantioselectivity in the solvents dichloromethane, chloroform, and methanol. Benzoic acid (numbers 1-3 and 10-12), p-toluenesulfonic acid (numbers 4-6 and 13-15), and triethylamine (numbers 7-9 and 16-18) were added to further optimize the reaction. As shown in Table 2, when methanol was used as the solvent and benzoic acid was used as the co-catalyst, the ee value reached 97% and the dr value reached 81 / 19. When chloroform was used as the solvent and benzoic acid was used as the co-catalyst, the ee value also reached 86% and the dr value reached 80 / 20.

[0063] Table 2 Effects of different additives on Michael addition reaction catalyzed by supported catalysts

[0064]

[0065] Example 9. Preparation of (S)-2-((R)-2-nitro-1-phenylethyl)cyclohexan-1-one (Extension of catalytic substrate)

[0066] Add Poly-2 to a 10 mL single-necked bottle. 200 To the reaction mixture were added benzoic acid (12.21 mg, 0.10 mmol) and cyclohexanone (78.52 mg, 0.80 mmol). The mixture was stirred at room temperature for 1 h, and then trans-β-nitrostyrene (29.83 mg, 0.20 mmol) was added. The mixture was stirred at 25°C for 5 days. After completion of the reaction, the mixture was centrifuged, dried, and the catalyst recovered. The filtrate was extracted with dichloromethane, concentrated, and purified by column chromatography to obtain (S)-2-((R)-2-nitro-1-phenylethyl)cyclohexan-1-one in a yield of 78%, an ee value of 97%, and a dr value of 81 / 19. HPLC conditions were as follows: Chiralpak AS-H column; n-hexane / isopropanol = 90 / 10 (v / v); flow rate 1.00 mL / min; wavelength 254 nm; 25°C; t R1 (syn.)=11.78min,t R2 (syn.)=13.81min,t R1 (anti.)=15.87min,t R2 (anti.) = 17.57 min; the reaction formula is as follows:

[0067]

[0068] Michael Addition Reaction of Cyclohexanone and Substituted β-Nitrostyrene Catalyzed by Supported Catalysts

[0069] Under the optimized conditions, 10 solvents were screened for each substituted β-nitrostyrene. Five solvents with relatively good performance are listed in Table 3. However, their ee values ​​were relatively low and further optimization is needed.

[0070] Table 3 Asymmetric Michael addition reactions of different substrates

[0071]

[0072] Example 10: Performance test of recovery and recycling of supported catalyst

[0073] To support the catalyst poly-2 200 Taking the Michael reaction of cyclohexanone and trans-β-nitrostyrene as an example, first weigh the catalyst poly-2 200To the reaction mixture was added 1 mL of methanol, stirred, then cyclohexanone (65.9 mg, 0.67 mmol), trans-β-nitrostyrene (25.0 mg, 0.17 mmol), and finally benzoic acid (21.0 mg, 0.17 mmol), and stirred at 25°C. After the reaction was completed, a large amount of ether was added to precipitate the polymer catalyst, centrifuged, and dried in vacuo. The reaction mixture was then recycled for the asymmetric Michael reaction of trans-β-nitrostyrene and cyclohexanone in methanol. The results are shown in Table 4. After the supported catalyst was recycled three times, the activity of the catalytic reaction and the stereoselectivity of the product did not decrease significantly.

[0074] Table 4 Supported catalyst poly-2 200 Table of cyclic catalytic results for Michael addition reaction

[0075]

[0076]

[0077] Examples 1 to 10 demonstrate the preparation and application of a chiral cyclohexanediamine-supported polyisonitrile catalyst of the present invention. The cyclohexanediamine-supported catalyst exhibits high catalytic activity and stereoselectivity. Under reasonable conditions of solvent and co-catalyst, the catalytic activity of the catalyst can be continuously optimized and has a wide range of applications. At the same time, the catalyst is easy to recover, and after multiple recycling, the activity of the catalytic reaction and the stereoselectivity of the product are maintained at a good level.

[0078] The above describes in detail the preferred embodiments of the present invention. It should be understood that numerous modifications and variations based on the concepts of the present invention can be made by those skilled in the art without inventive effort. Therefore, any technical solution that can be derived by those skilled in the art based on the concepts of the present invention through logical analysis, reasoning, or limited experimentation based on the existing technology should be within the scope of protection defined by the claims.

Claims

1. Application of a chiral cyclohexanediamine-supported polyisonitrile catalyst to asymmetric Michael addition reaction in different solvents and different co-catalysts, characterized in that: The preparation method of the chiral cyclohexanediamine-supported polyisonitrile catalyst specifically comprises the following steps: Step 1: Add chiral cyclohexanediamine isonitrile monomer and palladium initiator into a polymerization bottle; Step 2: Under anhydrous and oxygen-free conditions, the nitrogen atmosphere was replaced three times, and dry tetrahydrofuran was added under N2 flow; Step 3: react at 50-60 °C for 10-24 h, and then add methanol to terminate the reaction; Step 4: Add a large amount of ether to precipitate a solid; Step 5: Centrifuge the solid and vacuum dry it to constant weight to obtain the product poly-2 m ; The synthetic route of the preparation method is: ； The synthetic route of the chiral cyclohexanediamine isonitrile monomer is: ； The structural formula of the palladium initiator is: .

2. The use according to claim 1, characterized in that The specific application process is as follows: a certain amount of loaded catalyst, a certain amount of nitroolefin, and cyclohexanone are added to a reaction bottle, a certain amount of solvent is added, stirred at room temperature for a certain period of time, and then a certain amount of co-catalyst is added. The reaction is carried out at 25°C for a certain period of time, ether is added, centrifuged, dried, and the loaded catalyst is recovered; the filtrate is concentrated and separated by column chromatography to obtain the corresponding asymmetric Michael addition product.

3. The use according to claim 1, characterized in that The solvent is one of chloroform, 1,2-dichloroethane, ethanol, dichloromethane, toluene, methanol, saline, water, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide / water, acetonitrile, acetone, ethyl ether, 1,2-dichloroethane, dimethyl sulfoxide, isopropanol, ethyl acetate, N,N-dimethylformamide / water, n-hexane, dioxane, and carbon tetrachloride solution.

4. The use according to claim 1, wherein The co-catalyst is one of benzoic acid, trifluoroacetic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-methylbenzoic acid, 2-fluorobenzoic acid, phenol, 4-nitrophenol, 2,4,6-trinitrophenol, chloroacetic acid, n-octanoic acid, 4-nitrobenzoic acid, 4-fluorophenol, tetrafluoroboric acid, citric acid, hydrochloric acid, dodecylbenzenesulfonic acid, phosphoric acid, sulfuric acid, formic acid salicylic acid, propionic acid, 2,4-dichlorobenzoic acid, ammonium chloride, sodium sulfate, sodium carbonate, triethylamine, and diethylamine.

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