Ferrocenyl chiral diphosphine ligand and preparation method of intermediate thereof
By using a chiral catalyst with high catalytic activity and a simplified synthetic route, the synthesis problem of ferrocenyl chiral bisphosphine ligands was solved, and efficient preparation of products with high yield and high ee value was achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510952188.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-10
- Publication Date
- 2025-10-14
AI Technical Summary
The synthesis of existing ferrocenyl chiral bisphosphine ligands has the problems of great difficulty in controlling stereoselectivity, low yield, difficulty in separation and purification, and the traditional synthesis route has long steps, high risk and poor economic efficiency.
Using highly active chiral catalysts such as [Ir(COD)Cl]2 or [Rh(COD)Cl]2, (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine is prepared through a one-step asymmetric reductive amination reaction, followed by a simple splitting reaction. The one-pot method and Ullmann coupling reaction are combined to simplify the synthetic route and avoid the use of dangerous steps and high-risk materials.
The yield and economy are improved, the operation steps are simplified, the production cost is reduced, the efficient preparation of high ee value products is achieved, and it is suitable for scale-up production.
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Figure CN120774972A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a ferrocenyl chiral diphosphine ligand and an intermediate thereof. BACKGROUND
[0002] Ferrocene-based catalysts are mainly used in the field of organometallic chemistry, covering multiple industries, including automobiles, aerospace, medicine, agriculture, and environmental protection. Its unique chemical structure makes it widely used in catalysts, drugs, electrochemical materials, and other fields. Ferrocene is an organometallic compound with a sandwich structure, composed of two cyclopentadiene rings connected by an iron atom. This structure endows it with aromaticity, stability, low toxicity, and redox reversibility, making it one of the important research topics in modern chemistry. Because the iron atom in its molecule can serve as a source of iron elements in the body, the biological and physiological activity of ferrocene and its derivatives has also attracted great attention from scientists.
[0003] However, the synthesis of such ligands still has many difficulties. For example, when synthesizing chiral ferrocenyl phosphine ligands, it is necessary to design a chiral induction strategy (such as using a chiral ligand precursor or an asymmetric synthesis method), but the control of stereoselectivity is difficult, and the yield is often low; in addition, due to the presence of special structural units that are sensitive to air or water, the separation and purification of the product also become a difficulty.
[0004] (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine and its derivatives are a class of ferrocenyl chiral diphosphine ligands with high catalytic activity. The traditional preparation method of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine is as follows: 1. In the existing patent CN116410240A, acetylferrocene is reduced to 1-ferrocenylethanol under the catalysis of CBS catalyst and BH3-SMe2; then, 1-ferrocenylethanol reacts with acetic anhydride and dimethylamine respectively to prepare (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine with low ee value; finally, the product with high ee value is obtained after resolution by chiral resolving agent tartaric acid and dissociation. 2. Different from the first method, acetyl is reduced to 1-ferrocenylethanol by Red-Al, and the remaining steps are the same (Synthesis 2023; 55(15): 2390-2396, DOI: 10.1055 / s-0042-1751393).
[0005] The existing compound (1R,1″R)-2,2″-bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP ((1R,1″R)-2,2″-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP), cas: 137096-37-8, has currently mainly two synthetic routes:
[0006]
[0007] First, (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine is iodinated by sec-butyllithium and iodine, and then reacted with iodomethane to form a quaternary ammonium salt, followed by reaction with lithium diphenylphosphide to obtain a coupling product by nickel and zinc synergistic catalysis, and finally the final product is obtained by reduction with trichlorosilane.
[0008]
[0009]
[0010] Another is also started from (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine, and then reacted with diphenylphosphine hydrogen to obtain an intermediate, followed by complexing borane and preparing Grignard, and finally the target product is obtained by Grignard coupling and then deboronation.
[0011] Currently, the traditional synthetic route of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine uses CBS catalyst to catalyze borane to reduce the carbonyl group, and then reacts with acetic anhydride / dimethylamine to obtain a crude product. The catalyst has a large amount of use and the overall route is long, and finally a high ee value product can be obtained only by further separation, which greatly reduces the operability of its scale-up production. The synthesis of Ph-TRAP (CAS: 137096-37-8) has a long overall step, needs an additional reduction step, and some reactions have high risk and low operability, the overall yield of the route is low, and the economy is poor. SUMMARY
[0012] The application provides a preparation method of a ferrocenyl chiral biphosphine ligand and an intermediate thereof, and has the advantages of cheap and easily available raw materials, less chiral catalyst consumption, less preparation steps, high product yield and good quality.
[0013] Technical scheme: In order to achieve the above-mentioned purpose, the application provides a preparation method of (S)-(-)-N,N-dimethyl-1-ferrocenyl ethylamine ligand, comprising the following steps:
[0014] Under the atmosphere of inert gas, acetylferrocene and a chiral catalyst are dissolved in an organic solvent, and then dimethylamine organic solvent is added dropwise, followed by continuous reaction, and then the crude product of N,N-dimethyl-1-ferrocenyl ethylamine is obtained through purification, and then (S)-(-)-N,N-dimethyl-1-ferrocenyl ethylamine is obtained through resolution and dissociation of a chiral resolution agent.
[0015] Under the atmosphere of inert gas, acetylferrocene and a chiral catalyst are dissolved in an organic solvent, and then dimethylamine organic solvent is added dropwise, followed by continuous reaction, and then the crude product of N,N-dimethyl-1-ferrocenyl ethylamine is obtained through purification, and then (S)-(-)-N,N-dimethyl-1-ferrocenyl ethylamine is obtained through resolution and dissociation of a chiral resolution agent.
[0016] The chiral catalyst is 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2) or 1,5-cyclooctadiene rhodium chloride dimer ([Rh(COD)Cl]2) or the like.
[0017] The ligand is NMe-XiangPhos, NMe-Xu1, NMe-Xu6 or NMe-Xu2 or the like.
[0018] The molar ratio of the acetylferrocene, the chiral catalyst, the ligand and the dimethylamine is 1:0.002-0.5:0.01-1.0:1.0-5.0.
[0019] The reaction formula of the reaction is as follows:
[0020]
[0021] The preparation method of the ferrocenyl biphosphine ligand of the application dissolves the synthesized (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand in an organic solvent, adds sec-butyllithium dropwise under low temperature conditions, continues the reaction, adds an organic solvent solution of iodine dropwise under low temperature conditions, continues the reaction, and obtains an iodination product; then the iodination product undergoes Ullmann reaction under nickel catalysis to obtain a coupling product; finally, the coupling intermediate and diphenylphosphine are dissolved in acetic acid, and the reaction is continued to obtain the target product.
[0022] The (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand is dissolved in anhydrous diethyl ether, sec-butyllithium is added dropwise under the condition of-50-0℃, the reaction is continued for 3-18h, iodine tetrahydrofuran solution is added dropwise under the condition of-50-0℃, the reaction is continued for 12-24h, and the iodination product is obtained.
[0023] The molar ratio of the (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand, sec-butyllithium, and iodine is 1:1.0-2.4:1.0-3.0.
[0024] The iodination product catalytically undergoes Ullmann reaction under the condition of no solvent, nickel bromide, zinc powder, and tetrabutylammonium iodide to obtain a coupling product, and the reaction is continued for 6-18h under the condition of 40-120℃ to obtain the target product; the molar ratio of the iodination product, nickel bromide, zinc powder, tetrabutylammonium iodide, and tetrabutylammonium bromide is 1:0.03-1.0:0.1-10.0:0.1-0.5.
[0025] The coupling intermediate and diphenylphosphine are refluxed in acetic acid for 12-48h to obtain the final product; the molar ratio of the coupling intermediate and diphenylphosphine is 1:0.8-2.0.
[0026] As a preference, the reaction formula of the reaction is as follows:
[0027]
[0028] Currently, the traditional synthetic route of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine uses CBS catalyst to catalyze borane to reduce the carbonyl group, and then reacts with acetic anhydride / dimethylamine to obtain a crude product. The catalyst has a large amount of use, the overall route is long, and the product with high ee value can be finally obtained only by further separation, which greatly reduces the operability of the large-scale production. The synthesis of (1R,1″R)-2,2″-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8) has a long overall step, needs an additional reduction step, and has high danger and low operability in some reactions. The total yield of the route is low, and the economy is poor.
[0029] In the preparation process of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine, the present application uses a chiral catalyst with high catalytic activity, and the product of asymmetric reductive amination can be obtained in one step. Then, the product with high ee value can be obtained by simple separation. At the same time, the present application adopts one-pot preparation, which is simple to operate and has high yield, avoids product loss or deterioration in the transfer and purification process, and is convenient for large-scale production. At the same time, in the preparation process, the coupling step with relatively low yield is placed in the front (the second step of the present application, the fourth step of the first synthesis method of background technology Ph-TRAP, which saves material and step cost; the method of directly reacting diphenylphosphine with (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine is used, without the need for additional preparation of quaternary ammonium salt and lithium diphenylphosphine.
[0030] In the synthesis of (1R,1″R)-2,2″-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8), the Ullmann coupling is used. Compared with other methods, the present application places the coupling step with relatively low yield in the second step, which improves the material and step economy; further reaction: the present application directly reacts diphenylphosphine with the coupling product, which avoids the preparation of quaternary ammonium salt and phosphine lithium compared with other methods, and has simple steps, good operation safety, strong implementability, and is conducive to large-scale production. The synthesis of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine by the method of the present application can shorten the synthesis route of the compound (1R,1″R)-2,2″-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8), and can significantly improve the yield and economy.
[0031] The present application discards the traditional two-step reduction + amination method in the synthesis of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine, and uses a high-activity chiral catalyst to achieve one-step reductive amination synthesis, which not only improves the economy and yield, but also provides convenience for the subsequent chiral resolution. In the synthesis of (1R,1″R)-2,2″-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8), (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine is used as a starting material, and only three steps of iodination, coupling and reduction can achieve the synthesis route of 6 steps or more required by the traditional route, and no dangerous process is involved, which improves the safety.
[0032] In addition, in the synthesis of the intermediate of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine, the activity gap between the chiral catalysts [Ir(COD)Cl]2 and [Rh(COD)Cl]2, [Ir(COD)Cl]2 can obtain the product with relatively higher yield; the type of solvent has a slight greater influence on the reaction, and the amount of catalyst and ligand has no obvious promoting effect on the reaction.
[0033] In the synthesis of the intermediate of Ph-TRAP, the catalytic effect of anhydrous copper chloride is significantly lower than that of anhydrous nickel chloride; the use of manganese powder for reduction, the change of the type of ammonium salt and the type of solvent all have certain inhibitory effect on the reaction.
[0034] Advantages: Compared with the prior art, the present application has the following obvious advantages:
[0035] In the synthesis of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine, acetylferrocene is used as a starting material, tetrahydrofuran is used as a solvent, dimethylamine is slowly added, and the reductive amination product is obtained after continuous reaction; then simple filtration, liquid separation and concentration are carried out to obtain the intermediate; then the intermediate is reacted with tartaric acid for resolution, and the product with high ee value is obtained after filtration and dissolution with sodium hydroxide solution. Among them, the asymmetric reductive amination: unlike the traditional step of first reducing to alcohol with borane and then amination, the present application uses a chiral catalyst to perform amination in one step, which greatly saves the cost of raw materials and steps; further chiral resolution: since the present application obtains a relatively high ee value product in the previous step, simple resolution can obtain a product with an ee value greater than 99%.
[0036] In the synthesis of (1R,1''R)-2,2''-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1''-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8), (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine is used as a starting material, and the synthesis route of 6 steps or more required by the traditional route can be realized in only three steps of iodination, coupling and reduction, and no dangerous process is involved, which improves safety. BRIEF DESCRIPTION OF DRAWINGS
[0037] Figure 1 NMR spectrum of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine synthesized in the present application;
[0038] Figure 2 NMR spectrum of (1R,1''R)-2,2''-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1''-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8) synthesized in the present application;
[0039] Figure 3 NMR spectrum of (1R,1''R)-2,2''-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1''-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8) synthesized in the present application. DETAILED DESCRIPTION
[0040] The present application will be further described below in conjunction with examples.
[0041] The experimental methods described in the examples are all conventional methods unless otherwise specified; the materials, reagents, etc. used in the examples can be obtained from commercial channels unless otherwise specified.
[0042] Among them: the synthesis of ligands NMe-Xu2, NMe-Xu6, etc. uses the literature: Ir / XuPhos-catalyzed direct asymmetric reductive amination of ketones with secondary amines, Zhang J-Let. al, Org. Chem. Front., 2024, 11, 6735.
[0043] Example 1
[0044] Preparation of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine
[0045] Step one: In a flask, add acetylferrocene 8.0 g, [Ir(COD)Cl] 20.05 g, ligand NMe-Xu 20.2 g, replace argon three times, add anhydrous tetrahydrofuran 100 ml, under ice water bath condition, cool to 0 °C, after stirring for 30 minutes, add 50.0 ml 1.3M dimethylamine tetrahydrofuran solution drop by drop, then restore to room temperature and continue to react for 12 h; after the reaction is completed, add 50 ml water and 100 ml dichloromethane to separate, then extract twice with 100 ml dichloromethane each time, combine the organic phase, dry with anhydrous sodium sulfate, filter and concentrate to obtain brown viscous liquid intermediate 8.03 g, with a yield of 89%. Element analysis theory C: 65.40, H: 7.39; measured C: 65.11, H: 7.33.
[0046] Step two: In a flask, add ferrocene intermediate 8.03 g obtained in step one, L-tartaric acid 7.03 g, replace argon three times, add anhydrous methanol 150 ml, stir for 12 h, then filter to obtain filter cake, wash twice with 20 ml methanol; then dissolve the filter cake in 200 ml dichloromethane, add 50 ml 1M sodium hydroxide solution drop by drop, continue to stir for 2 h, then separate, extract the aqueous phase twice with dichloromethane, combine the organic phase, dry and filter, and concentrate to obtain brown viscous liquid (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine 7.47 g, with a yield of 93%. Element analysis theory C: 65.40, H: 7.39; measured C: 65.23, H: 7.29, see the nuclear magnetic resonance spectrum in the attached figure. Figure 1 .
[0047] 1 HNMR (CDCI3): 4.11-4.06 (m, 9H), 3.56 (q, J = 6.9 Hz, 1H), 2.05 (s, 6H), 1.41 ppm (d, J = 6.9 Hz, 3H).
[0048] Comparative example 1
[0049] In a flask, add acetylferrocene 8.0 g, [Rh(COD)Cl] 20.05 g, ligand NMe-Xu 20.2 g, replace argon three times, add anhydrous tetrahydrofuran 100 ml, under ice water bath condition, cool to 0 °C, after stirring for 30 minutes, add 50.0 ml 1.3M dimethylamine tetrahydrofuran solution drop by drop, then restore to room temperature and continue to react for 12 h; after the reaction is completed, add water and dichloromethane to separate, then extract twice with dichloromethane, combine the organic phase, dry with anhydrous sodium sulfate, filter and concentrate to obtain brown viscous liquid intermediate 5.10 g, with a yield of 56.7%.
[0050] Comparative Example 2
[0051] A 3-necked flask was charged with acetylferrocene 8.0 g, [Ir(COD)Cl]2 20.05 g, ligand NMe-Xu 60.22 g, and purged with argon three times. Anhydrous tetrahydrofuran 100 ml was added, and the mixture was cooled to 0 °C under an ice-water bath. After stirring for 30 min, 50.0 ml of 1.3 M dimethylamine tetrahydrofuran solution was added dropwise, and the mixture was allowed to react at room temperature for 12 h. After the reaction was completed, the mixture was partitioned between water and dichloromethane, and the organic phase was extracted twice with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give brown viscous liquid intermediate 7.94 g in 88% yield.
[0052] Comparative Example 3
[0053] A 3-necked flask was charged with acetylferrocene 8.0 g, [Ir(COD)Cl]2 20.05 g, ligand NMe-Xu 60.22 g, and purged with argon three times. Anhydrous tetrahydrofuran 100 ml was added, and the mixture was cooled to 0 °C under an ice-water bath. After stirring for 30 min, 50.0 ml of 1.3 M dimethylamine tetrahydrofuran solution was added dropwise, and the mixture was allowed to react at room temperature for 12 h. After the reaction was completed, the mixture was partitioned between water and dichloromethane, and the organic phase was extracted twice with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give brown viscous liquid intermediate 7.94 g in 88% yield.
[0054] Comparative Example 4
[0055] A 3-necked flask was charged with acetylferrocene 8.0 g, [Ir(COD)Cl]2 20.05 g, ligand NMe-Xu 60.22 g, and purged with argon three times. Anhydrous tetrahydrofuran 100 ml was added, and the mixture was cooled to 0 °C under an ice-water bath. After stirring for 30 min, 50.0 ml of 1.3 M dimethylamine tetrahydrofuran solution was added dropwise, and the mixture was allowed to react at room temperature for 12 h. After the reaction was completed, the mixture was partitioned between water and dichloromethane, and the organic phase was extracted twice with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give brown viscous liquid intermediate 7.94 g in 88% yield.
[0056] Comparative Examples 1-4 are comparative examples of Step 1 in Example 1, and other steps are the same as in Example 1. It can be seen from Comparative Example 1 that there is a difference in activity between the two chiral catalysts [Ir(COD)Cl]2 and [Rh(COD)Cl]2, and [Ir(COD)Cl]2 can obtain the product with a relatively higher yield. It can be seen from Comparative Example 2 that the effects of the two ligands NMe-Xu2 and NMe-Xu6 are similar. It can be seen from Comparative Example 3 that the type of solvent has a slight greater effect on the reaction, and using anhydrous ethanol as the solvent can greatly reduce the yield of the reaction. It can be seen from Comparative Example 4 that increasing the amount of catalyst and ligand does not have an obvious promoting effect on the reaction.
[0057] Example 2
[0058] Preparation of (1R,1"R)-2,2"-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1"- biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8)
[0059] Step one: A 3-necked flask was charged with (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine 15.0 g, argon was replaced for three times, ethyl ether 200 ml was added, dry ice acetone bath was used to cool the mixture to below -50 °C, 50 ml 1.5 M sec-butyllithium in n-hexane was added dropwise, then the mixture was allowed to warm to room temperature and stirred for 3 h, then a solution of 17.8 g iodine in 100 ml tetrahydrofuran was added dropwise at below -30 °C, the mixture was allowed to warm to room temperature and stirred for 24 h, after quenching with sodium sulfite, 200 ml water and 100 ml dichloromethane were added and the mixture was partitioned, the organic layer was dried, filtered and concentrated to give 17.5 g of intermediate 1 as a brown solid in 78% yield.
[0060] Step two: A 3-necked flask was charged with intermediate 1 17.5 g, anhydrous nickel chloride 0.35 g, zinc powder 0.62 g, tetrabutylammonium iodide 2.36 g, argon was replaced for three times, tetrahydrofuran 200 ml was added, the mixture was stirred until homogeneous, then tetrahydrofuran was evaporated, the mixture was allowed to warm to 60 °C and stirred for 12 h, after cooling to room temperature, the mixture was filtered through a Buchner funnel, the filtrate was partitioned with 200 ml water and 100 ml dichloromethane, the organic layer was dried, filtered and purified by column chromatography to give 13.5 g of intermediate 2 as an orange solid in 58% yield.
[0061] Step three: A 3-necked flask was charged with intermediate 2 13.5 g, diphenylphosphine 7.4 g, argon was replaced for three times, acetic acid 100 ml was added, the mixture was allowed to warm to 100 °C and stirred for 12 h, after cooling to room temperature, the acetic acid was evaporated to give a crude product, which was recrystallized from methanol to give the target product 17.4 g in 83% yield. 1 H NMR, 31 PNMR nuclear magnetic resonance spectrum is shown in the attached figure Figure 2 and Figure 3 .
[0062] 1 H NMR (C6D6): 7.58-7.46 (m, 4H), 7.10-6.96 (m, 6H), 4.47 (s, 1H), 4.22 (s, 5H), 3.99 (t, J = 2.4 Hz, 1H), 3.82 (s, 1H), 3.70 (q, J = 6.9 Hz, 1H), 1.52-1.46 ppm (m, 3H).
[0063] 31PNMR (C6D6): 1.16 ppm.
[0064] Comparative Example 5
[0065] A 3-necked flask was charged with intermediate 1 17.5 g, anhydrous copper chloride 0.32 g, zinc powder 0.62 g, tetrabutylammonium iodide 2.36 g, and replaced with argon three times. Tetrahydrofuran 200 ml was added, and after stirring uniformly, the tetrahydrofuran was evaporated. Subsequently, the reaction was carried out at an external temperature of 60 °C for 12 h. After the reaction was completed and the temperature was cooled to room temperature, the reaction mixture was filtered through a Buchner funnel. The filtrate was partitioned with water and dichloromethane, and after extraction, drying, and filtration, column chromatography was carried out to obtain 4.7 g of intermediate 2 as an orange solid, with a yield of 20.2%.
[0066] Comparative Example 6
[0067] A 3-necked flask was charged with intermediate 1 17.5 g, anhydrous nickel chloride 0.35 g, manganese powder 0.60 g, tetrabutylammonium iodide 2.36 g, and replaced with argon three times. Tetrahydrofuran 200 ml was added, and after stirring uniformly, the tetrahydrofuran was evaporated. Subsequently, the reaction was carried out at an external temperature of 60 °C for 12 h. After the reaction was completed and the temperature was cooled to room temperature, the reaction mixture was filtered through a Buchner funnel. The filtrate was partitioned with water and dichloromethane, and after extraction, drying, and filtration, column chromatography was carried out to obtain 9.9 g of intermediate 2 as an orange solid, with a yield of 42.5%.
[0068] Comparative Example 7
[0069] A 3-necked flask was charged with intermediate 1 17.5 g, anhydrous nickel chloride 0.35 g, zinc powder 0.62 g, tetrabutylammonium bromide 1.99 g, and replaced with argon three times. Tetrahydrofuran 200 ml was added, and after stirring uniformly, the tetrahydrofuran was evaporated. Subsequently, the reaction was carried out at an external temperature of 60 °C for 12 h. After the reaction was completed and the temperature was cooled to room temperature, the reaction mixture was filtered through a Buchner funnel. The filtrate was partitioned with water and dichloromethane, and after extraction, drying, and filtration, column chromatography was carried out to obtain 13.1 g of intermediate 2 as an orange solid, with a yield of 56%.
[0070] Comparative Example 8
[0071] A 3-necked flask was charged with intermediate 1 17.5 g, anhydrous nickel chloride 0.35 g, zinc powder 0.62 g, tetrabutylammonium iodide 2.36 g, and replaced with argon three times. Tetrahydrofuran 200 ml was added, and after stirring uniformly, the tetrahydrofuran was evaporated. Subsequently, the reaction was carried out at an external temperature of 60 °C for 12 h. After the reaction was completed and the temperature was cooled to room temperature, the reaction mixture was filtered through a Buchner funnel. The filtrate was partitioned with water and dichloromethane, and after extraction, drying, and filtration, column chromatography was carried out to obtain 11.7 g of intermediate 2 as an orange solid, with a yield of 50%.
[0072] Comparative Examples 5-8 are comparative examples for Step 2 in Example 2, and the other steps are the same as in Example 2. As can be seen from Comparative Example 5, the catalytic effect of anhydrous copper chloride is significantly lower than that of anhydrous nickel chloride. As can be seen from Comparative Examples 6, 7, and 8, the use of manganese powder for reduction, the change in the type of ammonium salt, and the change in the type of solvent all have certain inhibitory effects on the reaction.
[0073] Comparative Example 9
[0074] In a flask, add intermediate 13.5 g, diphenylphosphine 9.9 g, replace argon three times, add acetic acid 150 ml, external temperature 100 °C reflux reaction for 12 h, after the reaction is completed, cool to room temperature, spin dry acetic acid to obtain the crude product, then recrystallize with methanol to obtain the target product 17.1 g, yield 81%.
[0075] Comparative Example 10
[0076] In a flask, add intermediate 13.5 g, diphenylphosphine 7.4 g, replace argon three times, add acetic acid 100 ml, external temperature 100 °C reflux reaction for 48 h, after the reaction is completed, cool to room temperature, spin dry acetic acid to obtain the crude product, then recrystallize with methanol to obtain the target product 17.4 g, yield 83%.
[0077] Comparative Examples 9-10 are the comparison of step three in Example 2, other steps are the same as Example 2, increasing the amount of acetic acid and reaction time will not affect the yield of the reaction.
[0078] Example 3
[0079] Preparation of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine
[0080] Step one: In a flask, add acetylferrocene 8.0 g, [Ir(COD)Cl] 20.05 g, ligand NMe-Xu 60.2 g, replace argon three times, add anhydrous 1,4-dioxane 100 ml, cool to 0 °C under ice water bath conditions, stir for 30 min, then add 50.0 ml of 1.3 M dimethylamine tetrahydrofuran solution dropwise, then restore to room temperature and continue to react for 12 h; after the reaction is completed, add 50 ml of water and 100 ml of dichloromethane, separate, then extract twice with 100 ml of dichloromethane each time, combine the organic phase, dry with anhydrous sodium sulfate, filter and concentrate to obtain brown viscous liquid intermediate 4.6 g, yield 51.0%.
[0081] Step two: In a flask, add the ferrocene intermediate obtained in step one 4.6 g, L-tartaric acid 6.28 g, replace argon three times, add anhydrous methanol 100 ml, stir for 12 h, then filter the filter cake with a Buchner funnel, wash twice with 20 ml of methanol; then dissolve the filter cake in 100 ml of dichloromethane, add 50 ml of 1M sodium hydroxide solution dropwise, continue to stir for 2 h, then separate, extract the aqueous phase with 50 ml of dichloromethane twice, combine the organic phase, dry, filter and concentrate to obtain brown viscous liquid (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine 4.24 g, yield 95.1%.
[0082] Example 4
[0083] Preparation of (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine
[0084] Step one: In a flask, add acetylferrocene 8.0 g, [Ir(COD)Cl] 20.02 g, ligand NMe-Xu 60.11 g, replace argon three times, add anhydrous ethyl ether 100 ml, cool to 0 °C under ice water bath, after stirring for 30 min, add 33.5 ml of 1.3M dimethylamine tetrahydrofuran solution drop by drop, then restore to room temperature and continue to react for 12 h; after the reaction is completed, add 50 ml water and 100 ml dichloromethane, separate, then extract twice with 100 ml dichloromethane each time, combine the organic phase, dry with anhydrous sodium sulfate, filter and concentrate to obtain brown viscous liquid intermediate 5.32 g, with a yield of 59.2%.
[0085] Step two: In a flask, add ferrocene intermediate 5.32 g obtained in step one, L-tartaric acid 6.67 g, replace argon three times, add anhydrous methanol 120 ml, stir for 12 h, then filter the filter cake with a Buchner funnel, wash twice with 20 ml of methanol; then dissolve the filter cake in 130 ml of dichloromethane, add 50 ml of 1M sodium hydroxide solution drop by drop, continue to stir for 2 h, then separate, extract the aqueous phase twice with 50 ml of dichloromethane, combine the organic phase, dry and filter, then concentrate to obtain brown viscous liquid (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine 4.97 g, with a yield of 94.8%.
[0086] As can be further seen from Examples 3 and 4, the type of solvent in step one in Example 1 has a slight greater influence on the reaction, and the use of anhydrous 1,4-dioxane or anhydrous ethyl ether as the solvent will greatly reduce the yield of the reaction.
[0087] Example 5
[0088] Preparation of (1R,1″R)-2,2″-Bis[(1R)-1-(diphenylphosphino)ethyl]-1,1″-biferrocene, (R,R)-(S,S)-PhTRAP (cas: 137096-37-8)
[0089] Step one: A 3-necked flask was charged with (S)-(-)-N,N-dimethyl-1- ferrocenylethylamine 15.0 g, replaced with argon three times, added anhydrous tetrahydrofuran 200 ml, cooled to below -50 °C with dry ice acetone bath, added 55 ml of 1.5 M sec-butyllithium n-hexane solution dropwise, then restored to room temperature and reacted for 3 h, then added 19.5 g of iodine dissolved in 100 ml of tetrahydrofuran at below -30 °C dropwise, and continued to react for 24 h. After quenching with sodium sulfite, 200 ml of water and 100 ml of dichloromethane were added and separated, and after drying and filtering, 17.7 g of brown solid was obtained as intermediate 1, with a yield of 78.9%.
[0090] Step two: A 3-necked flask was charged with intermediate 1 17.7 g, anhydrous nickel chloride 0.35 g, zinc powder 0.62 g, and tetrabutylammonium bromide 1.92 g, replaced with argon three times, added tetrahydrofuran 200 ml, stirred uniformly, then evaporated tetrahydrofuran, then reacted at 60 °C for 12 h, after the reaction was completed and cooled to room temperature, filtered with a Buchner funnel, the filtrate was separated with water and dichloromethane, extracted, dried and filtered, and then column chromatography was performed to obtain 14.0 g of orange solid as intermediate 2, with a yield of 60.1%.
[0091] Step three: A 3-necked flask was charged with intermediate 2 14.0 g and diphenylphosphine 7.4 g, replaced with argon three times, added acetic acid 100 ml, reacted at 100 °C for 12 h, after the reaction was completed and cooled to room temperature, the acetic acid was evaporated to obtain a crude product, then recrystallized with methanol to obtain the target product 17.7 g, with a yield of 85.1%.
Claims
1. A method for preparing a (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand, characterized in that: The steps include: Under an inert gas atmosphere, acetylferrocene and a chiral catalyst are dissolved in an organic solvent. After the ligand is added, an organic solvent solution containing dimethylamine is added dropwise, and the reaction is continued. After the reaction is completed, the crude product of N,N-dimethyl-1-ferrocenylethylamine is obtained through purification, and then the crude product is resolved and dissociated with a chiral resolving agent to obtain (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine.
2. The method for preparing the (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand according to claim 1, characterized in that: Under argon protection, acetylferrocene and a chiral catalyst are dissolved in anhydrous tetrahydrofuran, and dimethylamine in anhydrous tetrahydrofuran is added dropwise at -20 to 10°C. The reaction is then continued for 12 to 72 hours. After the reaction is completed, the crude product of N,N-dimethyl-1-ferrocenylethylamine is purified and then resolved and dissociated with a chiral resolving agent, L-tartaric acid, to obtain (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine.
3. The method for preparing the (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand according to claim 1 or 2, characterized in that: The chiral catalyst is 1,5-cyclooctadiene iridium chloride dimer or 1,5-cyclooctadiene rhodium chloride dimer.
4. The method for preparing the (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand according to claim 1 or 2, characterized in that: The ligand is preferably NMe-XiangPhos, NMe-Xu1, NMe-Xu6 or NMe-Xu2.
5. The method for preparing the (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand according to claim 1 or 2, characterized in that: The molar ratio of the acetylferrocene, the chiral catalyst, the ligand and the dimethylamine is 1:0.002-0.5:0.01-1.0:1.0-5.
0.
6. A method for preparing a ferrocenyl bisphosphine ligand, characterized in that: The (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand synthesized in claim 1 is dissolved in an organic solvent, sec-butyl lithium is added dropwise under low temperature conditions, and the reaction is continued. An iodine organic solvent solution is added dropwise under low temperature conditions, and the reaction is continued to obtain an iodinated product; the iodinated product then undergoes an Ullmann reaction under nickel catalysis to obtain a coupling product; finally, the coupling intermediate and diphenylphosphine are dissolved in acetic acid, and the reaction is continued to obtain the target product.
7. The method for preparing a ferrocenyl bisphosphine ligand according to claim 6, wherein: The (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand is dissolved in anhydrous ether, sec-butyl lithium is added dropwise at -50 to 0°C, the reaction is continued for 3 to 18 hours after returning to room temperature, and an iodine tetrahydrofuran solution is added dropwise at -50 to 0°C, and the reaction is continued for 12 to 24 hours to obtain an iodinated product.
8. The method for preparing a ferrocenyl bisphosphine ligand according to claim 6, wherein: The molar ratio of the (S)-(-)-N,N-dimethyl-1-ferrocenylethylamine ligand, sec-butyl lithium and iodine is 1:1.0-2.4:1.0-3.
0.
9. The method for preparing a ferrocenyl bisphosphine ligand according to claim 6, wherein: The iodide is catalyzed by an Ullmann reaction in the presence of nickel bromide, zinc powder, and tetrabutylammonium iodide in the absence of a solvent to obtain a coupling product, which is reacted at 40-120° C. for 6-18 hours to obtain a target product; the molar ratio of the iodide to nickel bromide, zinc powder, and tetrabutylammonium iodide is 1:0.03-1.0:0.1-10.0:0.1-0.
5.
10. The method for preparing a ferrocenyl bisphosphine ligand according to claim 6, wherein: The coupling intermediate and diphenylphosphine are refluxed in acetic acid for 12-48 hours to obtain a final product; the molar ratio of the coupling intermediate to diphenylphosphine is 1:0.8-2.0.