Binuclear iron catalyst as well as preparation method and application thereof
By utilizing the synergistic effect of a binuclear iron catalyst and a chiral phosphate BINOL ligand, the synthetic challenge of enantioselective insertion of iron catalysts into Si-H bonds was solved, achieving efficient and inexpensive synthesis of chiral organosilicon compounds with excellent yield and selectivity.
Patent Information
- Application Number
- CN202511493795.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-17
- Publication Date
- 2026-01-16
AI Technical Summary
Existing iron catalysts for enantioselective carbene insertion reactions of Si-H bonds suffer from problems such as a limited variety of chiral ligands, harsh reaction conditions, and high costs, and the application of noble metal catalysts such as iridium is also limited.
A binuclear iron catalyst was developed by preparing Salen ligand through the condensation reaction of ethylenediamine and salicylaldehyde, and then complexing it with anhydrous ferric chloride to form a binuclear iron catalyst Fe-1. This catalyst, combined with chiral phosphate BINOL ligand, is used to catalyze the enantioselective insertion reaction of Si-H bonds.
This method enables the efficient and inexpensive synthesis of chiral organosilicon compounds with a yield of up to 72%, an enantioselectivity of 97%, good environmental and biocompatibility, and reduced synthesis costs.
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Abstract
Description
TECHNICAL FIELD
[0001] The application relates to a binuclear iron catalyst and a preparation method and application thereof, and belongs to the technical field of organic synthesis. BACKGROUND
[0002] Chiral organosilicon compounds are widely used in the fields of biological medicine, organic synthesis and functional materials due to their unique physicochemical properties. The enantioselective carbene insertion reaction of a transition metal-catalyzed Si-H bond is one of the effective methods for synthesizing chiral organosilicon compounds. This method not only has mild reaction conditions and good atom economy, but also can realize the efficient synthesis of some chiral organosilicon compounds which are difficult to realize by traditional methods through the precise regulation of chiral ligands (Wang, Y. et al. Nat. Commun. 2019, 10, 1). Acc. Chem. Res .2012, 45 , 1365)。
[0003] .
[0004] Iron is a transition metal with abundant reserves, low price and little biological toxicity. In recent years, the Si-H bond insertion reaction based on iron carbene intermediates has attracted more and more attention, and some progress has been made in the iron-catalyzed diastereoselective carbene insertion reaction of Si-H bond (Wang, Y. et al. Nat. Commun. 2019, 10, 1). Chin. J. Org. Chem .2020, 40 , 873; J. Organomet. Chem .1995, 497 , 61; Org. Chem. Front 2017, 4 , 1917; Org. Lett .2017, 19 , 5736; Org. Lett .2018, 20 , 4641; RSC Adv .2019, 9 , 31241; ChemCatChem 2019, 11 , 5260; Org. Chem. Front .2024, 11 , 2241).
[0005] However, the development of the iron-catalyzed enantioselective carbene insertion reaction of Si-H bond is relatively slow. This is mainly due to the characteristics of iron, such as small atomic radius, open-shell electron structure, rich spin state and oxidation state. On the one hand, the types of chiral ligands suitable for iron are few, and at present, mainly some multidentate nitrogen ligands based on oxazoline skeleton (Wang, Y. et al. Nat. Commun. 2019, 10, 1). Org. Lett. 2018,20 On the other hand, iron is prone to spin state and oxidation state changes in the catalytic process, such as spin crossing, single electron transfer, etc. Angew. Chem. Int. Ed. 2024, 63 , e202402044; J. Am. Chem. Soc. 2021, 143 , 17793), resulting in unstable reaction intermediates and difficult identification, and unclear enantioselective control mechanism.
[0006] Xie and Lin group developed an enantioselective Si-H bond insertion reaction based on chiral spiro-bisoxazoline ligand (HMSI-BOX) and Fe(OTf)2 catalysis, and synthesized a series of chiral 2-aryl-2-silyl acetate derivatives with a yield of up to 99% and an ee value of up to 96% (Org. Lett. 2018, 20, 6544). Although this method is efficient, and is currently the only example of iron-catalyzed carbene enantioselective insertion into Si―H bond, the synthesis of chiral ligand has long steps and harsh reaction conditions, resulting in high synthesis cost. Org. Lett. 2018, 20 ,6544). Although this method is efficient, and is currently the only example of iron-catalyzed carbene enantioselective insertion into Si―H bond, the synthesis of chiral ligand has long steps and harsh reaction conditions, resulting in high synthesis cost.
[0007] .
[0008] Salen ligand is a derivative of one molecule of diamine and two molecules of salicylaldehyde, which is obtained by dehydration condensation. Its metal complexes have been widely used in many catalytic reactions due to its characteristics of cheap and easy to obtain, easy to control structure, and stable skeleton rigidity. For example, Katsuki group used 2 mol% of Salen-iridium chiral complex Ir(salen*) as catalyst, and successfully realized the high enantioselective Si―H bond insertion reaction between α-aryl-α-diazoacetate and α-alkyl-α-diazo compound and ArMe2SiH, PhRSiH2 for the first time, and excellent ee values were obtained for various α-diazo ester substrates (J. Am. Chem. Soc. 2010, 132, 4510). Although this method is efficient, the high cost of noble metal iridium and the difficulty in obtaining chiral salen ligand with binaphthalene skeleton seriously restrict its further application in industry. J. Am. Chem. Soc. 2010, 132 , 4510). Although this method is efficient, the high cost of noble metal iridium and the difficulty in obtaining chiral salen ligand with binaphthalene skeleton seriously restrict its further application in industry.
[0009] .
[0010] In order to overcome the shortcomings of the above-mentioned technologies, it is urgent to develop a simple and efficient, cheap and easy to obtain, and environmentally and biocompatible metal catalyst, which is coordinated with a cheap and easy to obtain chiral ligand, to realize the efficient synthesis of chiral organosilicon compounds. SUMMARY
[0011] Therefore, the application provides a dinuclear iron catalyst which has good catalytic performance for enantioselective carbene insertion reaction of Si-H bond and is environmentally and biologically compatible.
[0012] Specifically, the application is realized by the following scheme: A dinuclear iron catalyst, the structural formula of which is: .
[0013] The applicant also provides a preparation method of the above-mentioned dinuclear iron catalyst, the steps of which are as follows: Step one, condensation reaction of ethylenediamine and salicylaldehyde to obtain a Salen ligand; Step two, complexation reaction of the Salen ligand and anhydrous ferric chloride in the presence of a base agent and a solvent in an inert atmosphere to obtain a Salen ligand supported dinuclear iron catalyst, denoted as dinuclear iron catalyst Fe-1.
[0014] The above process can be expressed by the following reaction formula: .
[0015] Further, as a preferred: In step one, ethanol, methanol, isopropanol or the like is added as a solvent in the condensation reaction.
[0016] The molar ratio of ethylenediamine to salicylaldehyde is 1:2-3.
[0017] The reaction temperature of the condensation reaction is 50-70°C, and the reaction time is 2-6 h.
[0018] The condensation reaction can be carried out by the following process: salicylaldehyde and ethylenediamine are respectively dissolved in anhydrous ethanol to obtain solution A and solution B, solution A is added dropwise to solution B, stirring reaction, suction filtration, and the obtained solid is washed with cold ethanol and then vacuum suction filtered to obtain the Salen ligand.
[0019] In step two, The addition molar ratio of the Salen ligand to anhydrous ferric chloride is 1.5-1:1.
[0020] The inert atmosphere is any one of nitrogen, argon and air.
[0021] The base agent is any one of triethylamine, triisopropylamine and ethyl diisopropylamine.
[0022] The solvent is any one of ethanol, methanol and isopropanol.
[0023] The complexing reaction has a reaction temperature of 50-70℃ and a reaction time of 4-10 hours.
[0024] The applicant also provides an application of the above-mentioned binuclear iron catalyst in the synthesis of chiral organosilicon compounds.
[0025] As a specific case, in the above-mentioned application, a chiral organosilicon compound is obtained by using triethyl-substituted silane and α-phenyl-α-diazoacetic acid benzyl ester as raw materials, adding a chiral ligand and a binuclear iron catalyst, and catalyzing the reaction.
[0026] The catalytic reaction process can be expressed as follows: .
[0027] The chiral ligand is a chiral phosphoric acid (BINOL), and its structural formula is any one of the following structures: , and the target product can be obtained at a yield of 50-75% and an enantioselectivity of 25-97%, preferably L5, which can well control the yield (72%) and enantioselectivity (97% ee) of the product.
[0028] When the chiral ligand is particularly a chiral phosphoric acid, the amount of addition is 1-1.5 times the molar amount of the binuclear iron catalyst, and the catalyst in this range can ensure good reaction activity, and the reaction rate and conversion rate of the raw materials are both above 95%.
[0029] The amount of addition of the binuclear iron catalyst is 5-10 mol% of α-phenyl-α-diazoacetic acid benzyl ester.
[0030] The chloroalkane solvent is one of dichloromethane, 1,2-dichloroethane, and chloroform, and dichloromethane is preferred, which can well dissolve the iron catalyst and the ligand.
[0031] The triethyl-substituted silane is 2-4 times the molar amount of α-phenyl-α-diazoacetic acid benzyl ester, at which the reaction speed is fast and the reaction is stable, and the yield of the target product is as high as 72%.
[0032] On the basis of the above technical solution, we have made a systematic study on the temperature for synthesizing chiral organosilicon compounds, and determined that the preferred temperature range is above 35℃. When the reaction temperature for catalytic synthesis is 40-60℃, the yield of the product can be maintained in the range of 50-60%, but a too high temperature cannot significantly improve the yield, on the contrary, it additionally increases the energy consumption, which is not conducive to cost control; and when the reaction temperature is too low, such as 0-25℃, the reaction activity is poor, the reaction rate is reduced, and the raw materials cannot be completely converted. Therefore, the reaction temperature is preferably controlled at 30-35℃, and the reaction effect is better at 35℃. BRIEF DESCRIPTION OF DRAWINGS
[0033] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0034] Figure 1 This is an X-ray single-crystal image of the binuclear iron catalyst of this application; Figure 2 The infrared spectrum of the binuclear iron catalyst of this application; Figure 3 For the synthesis of chiral organosilicon compounds using the binuclear iron catalyst of this application 1 H spectrum; Figure 4 For the synthesis of chiral organosilicon compounds using the binuclear iron catalyst of this application 13 C spectrum; Figure 5 The HPLC spectrum of the chiral organosilicon compound synthesized using the binuclear iron catalyst of this application is shown. Detailed Implementation
[0035] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without creative effort are within the scope of protection of this application.
[0036] Example 1
[0037] This embodiment describes the preparation of Salen ligands, whose chemical name is: 2-[(1 E 5 E The preparation process of 6-(2-hydroxyphenyl)-2,5-diazahex-1,5-dien-1-yl]phenol is as follows: Salen ligand (2.2 mmol) and anhydrous FeCl3(2 mmol) were accurately weighed into a 25 mL Schlenk tube, a magnetic stirrer rotor was added, and the nitrogen was replaced three times. A solution was prepared by injecting 5 mL of methanol solution and 0.55 mL of triethylamine solution with a syringe, and the temperature was controlled at 60 °C, and the reaction was stirred for about 10 h until the solution changed color. After the reaction was completed, the product was completely precipitated, and was filtered. The filter cake was washed with 3x5 mL of cold methanol, and vacuum dried overnight to obtain the product, which was denoted as binuclear iron catalyst Fe-1.
[0038] The reaction formula of the above process is as follows: .
[0039] Product structure characterization: 1 H NMR (500 MHz, DMSO-d6)δ 13.41 (s, 2H), 8.58 (s, 2H), 7.43 (dd, J =8.0, 1.8 Hz, 2H), 7.33 (ddd, J = 9.1, 8.0, 1.8 Hz, 2H), 6.93 – 6.86 (m, 4H),3.92 (s, 4H). Example 2
[0040] This example prepares a binuclear iron catalyst, and the process is as follows: Salen ligand (2.2 mmol) and anhydrous FeCl3(2 mmol) were accurately weighed into a 25 mL Schlenk tube, a magnetic stirrer rotor was added, and the nitrogen was replaced three times. A solution was prepared by injecting 5 mL of methanol solution and 0.55 mL of triethylamine solution with a syringe, and the temperature was controlled at 60 °C, and the reaction was stirred for about 10 h until the solution changed color. After the reaction was completed, the product was completely precipitated, and was filtered. The filter cake was washed with 3x5 mL of cold methanol, and vacuum dried overnight to obtain the product, which was denoted as binuclear iron catalyst Fe-1.
[0041] The reaction formula of the above process is as follows: .
[0042] Since the trivalent iron has paramagnetism, it cannot be characterized by nuclear magnetic resonance.
[0043] Elemental analysis: C, 58.21; H, 4.27; N, 8.49; Found: C, 58.43; H, 4.40; N, 8.35. It is known that the purity of the binuclear iron catalyst Fe-1 is good.
[0044] From Figure 1 X-ray single crystal diagram confirms that the binuclear iron catalyst Fe-1 is a Salen-binuclear iron complex, in which two iron centers are bridged by an oxygen atom.
[0045] Example 3
[0046] This example carries out the synthesis of iron-catalyzed chiral organosilicon compounds, the process is as follows: Accurately weigh the binuclear iron catalyst Fe-1 (6.6 mg, 0.01 mmol) and chiral phosphoric acid (BINOL) ligand L5 (6.7 mg, 0.012 mmol) in turn, place them in a 25 mL dry Schlenk tube, add a magnetic stirrer, replace nitrogen three times, then add 2 mL dichloromethane in a nitrogen atmosphere, stir at room temperature for 10 minutes to fully complex the binuclear iron catalyst Fe-1 with the chiral phosphoric acid ligand L5. Then add α-phenyl-α-diazoacetic acid benzyl ester 2 (50.4 mg, 0.2 mmol) to the above mixture, stir vigorously for 10 minutes, control the temperature at 25°C or below, then add triethylsilane 1 (46.5 mg, 0.4 mmol), maintain the reaction temperature at 35°C, and stir the reaction for about 24 h. After the reaction is completed, the target product 3 is separated by column chromatography, the yield is 72%, the purity is 98%, and the ee=97% measured by HPLC.
[0047] The reaction formula of the above reaction process is as follows: .
[0048] The test results are shown in Table 1: Figures 2~5 1 H NMR (400 MHz, CDCl3)δ 7.41 – 7.32 (m, 7H), 7.31 – 7.24 (m, 2H),7.21 – 7.14 (m, 1H), 5.12 (s, 2H), 3.58 (s, 1H), 0.87 (t, J = 7.9 Hz, 9H),0.56 (ddd, J = 10.3, 7.9, 1.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 173.1, 136.5, 136.1, 128.6, 128.5, 128.2, 128.1, 125.6, 66.3, 42.8, 7.1, 2.7. HPLC (Chiralpak PA-2 columm, detected at 230 nm; hexane / 2-propanol = 98:2, 0.7 mL / min) retention times of 5.9 min (major) and 10.8 min (minor); [a] D 20 = +24.0 (c = 0.4, CH2Cl2); [a] D 20 = +23.0 ( c = 0.4, CH2Cl2) for (R) with 90% ee] (Org. Lett. 2018, 20, 6544). Example 3-1
[0049] This example is to screen the solvent, the process is as follows: This example is the same as the setting of Example 3, the difference is that dichloromethane is replaced by tetrahydrofuran, chloroform, 1,2-dichloroethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide and toluene, respectively, and the results are shown in Table 1.
[0050] Table 1: Reaction results of different solvents .
[0051] As can be seen from Table 1: chlorinated solvents such as dichloromethane, chloroform, 1,2-dichloroethane have better reaction results, especially when dichloromethane is used as the solvent, the conversion rate of diazo compound raw material 2 is high, the yield of target product 3 is good, and the enantioselectivity is excellent, so the reaction solvent is preferably dichloromethane. Using dichloromethane mainly solves the solubility problem of the catalyst, thereby reducing the occurrence of side reactions, which improves the yield.
[0052] In addition, when using tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide and toluene as solvents, the reaction effect is very poor and the yield is very low.
[0053] Example 3-2 This example is to screen the reaction temperature, the process is as follows: The present example and the setting of example 3 are the same, the difference is that the reaction temperature 35 ℃ is replaced by 25 ℃, 45 ℃, 55 ℃, 65 ℃ respectively, so that the reaction is carried out at different oil bath temperatures, and the results are shown in table 2.
[0054] Table 2: reaction results at different reaction temperatures .
[0055] From table 2, it can be seen that when the catalytic reaction temperature is room temperature (25 ℃), due to the incomplete conversion of raw material 2, the yield of target product 3 is only 45 %, but the enantioselectivity is as high as 97 %. In order to improve the conversion rate of raw material, the reaction temperature is increased to 35 ℃, at this time, the conversion of raw material 2 can reach 100 %, the yield of target product 3 can be improved to 72 %, and the enantioselectivity can still be maintained at 97 %. However, as the temperature continues to rise, the side reaction increases, and the enantioselectivity decreases. The possible reason is that diazonium compound is easy to decompose and inactivate at higher temperature. For example, when the reaction temperature is controlled at 45 ℃, 55 ℃ and 65 ℃ in turn, the yield of target product 3 is reduced to 68 %, 60 % and 45 % in turn, and the enantioselectivity is reduced from 92 % to 85 %. In view of the above, the reaction temperature is preferably 35 ℃.
[0056] Example 3-3 In this example, the screening of chiral phosphoric acid (BINOL) ligand is carried out, and the process is as follows: .
[0057] The present example and the setting of example 3 are the same, the difference is that under the same experimental conditions of binuclear iron catalyst Fe-1, solvent and reaction temperature, chiral ligand L5 is replaced by the same amount of L1~L4 and L6~L8 respectively, and the results are shown in table 3.
[0058] Table 3: reaction results of different chiral ligands .
[0059] From table 3, it can be seen that the reaction activity of chiral phosphoric acid (BINOL) ligand with electron donating group on the side arm benzene ring is better. When L1~L6 is used as ligand, the conversion of raw material 2 can reach 95 % and above, the yield of target product 3 can reach 52 ~ 80 %, and the enantioselectivity can still be maintained at 81 ~ 97 %. Especially when L6 is used as ligand, good yield and excellent enantioselectivity can be obtained at the same time. When the chiral phosphoric acid (BINOL) ligand with electron withdrawing group on the side arm benzene ring, the reaction activity is poor, and only medium yield and good enantioselectivity can be obtained. In view of the above, the chiral ligand of the reaction is preferably L5.
[0060] The synthesis route of the above chiral phosphoric acid (BINOL) ligand is as follows: .
[0061] The above examples only express several possible implementation manners of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the scope of the patent of the present application. The examples are not intended to limit the protection scope in the claims of the present application. For those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, and any equivalent implementation or change made without departing from the present application shall be included in the present application.
Claims
1. A dinuclear iron catalyst characterized in that, The structural formula of the binuclear iron catalyst is: 。 2. A process for the preparation of the dinuclear iron catalyst of claim 1, characterized in that, The steps are as follows: Step one, condensation reaction of ethylenediamine and salicylaldehyde to obtain a Salen ligand; Step two, complexation reaction of the Salen ligand and anhydrous ferric chloride in the presence of a base agent and a solvent in an inert atmosphere to obtain a Salen ligand supported binuclear iron catalyst.
3. The method for preparing a dual-core iron catalyst according to claim 1, characterized in that: The molar ratio of ethylenediamine to salicylaldehyde is 1:2-3.
4. The method for preparing a dual-core iron catalyst according to claim 1, characterized in that: The reaction temperature of the condensation reaction is 50-70°C, and the reaction time is 2-6 h.
5. The method for preparing a dual-core iron catalyst according to claim 1, characterized in that: The addition molar ratio of the Salen ligand to anhydrous ferric chloride is 1.5-1:
1.
6. The method of claim 1, wherein: The base agent is any one of triethylamine, triisopropylamine, and ethyl diisopropylamine, and the solvent is any one of methanol, ethanol, and isopropanol.
7. A method for preparing a dual-core iron catalyst according to claim 1, characterized in that: In the complexation reaction, the reaction temperature is 50-70°C, and the reaction time is 4-10 h.
8. Use of the binuclear iron catalyst of claim 1 in the synthesis of a chiral organosilicon compound.
9. Use according to claim 8, characterized in that: A chiral organosilicon compound is obtained by catalytic reaction of triethyl-substituted silane and α-phenyl-α-diazoacetic acid benzyl ester with a chiral ligand and a binuclear iron catalyst.
10. Use according to claim 8, characterized in that: The addition amount of the binuclear iron catalyst is 5-10 mol% of α-phenyl-α-diazoacetic acid benzyl ester.