N, P, O tridentate chiral ligand based on ferrocene skeleton
By developing N, P, O tridentate chiral ligand based on ferrocene framework, the problem of insufficient selectivity and stability of existing catalysts in asymmetric catalytic reactions is solved, and efficient in Sonogashira coupling reactions is achieved. Enantioselectivity and diastereoselectivity.
Patent Information
- Application Number
- CN202411650734.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-19
- Publication Date
- 2025-02-25
AI Technical Summary
There are few researches on existing N, O, and P tridentate chiral ligands, and existing catalysts have problems of insufficient selectivity and stability in asymmetric catalytic reactions.
A N,P,O tridentate chiral ligand based on the ferrocene backbone was developed, prepared by a specific synthetic route, and applied in the Sonogashira coupling reaction.
The chiral ligand exhibits excellent enantioselectivity and diastereoselectivity in the Sonogashira coupling reaction, significantly improving the optical purity of the product and having excellent reaction yields.
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Figure CN119504878A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic chemistry and relates to a novel N, P, O tridentate chiral ligand based on a ferrocene skeleton. Background Art
[0002] In the past few decades, the field of asymmetric catalysis has made rapid progress. Various types of chiral ligands have been successfully synthesized and widely used in asymmetric catalytic reactions. These chiral ligands not only enrich the toolbox of asymmetric catalysis, but also significantly improve the enantioselectivity and diastereoselectivity of the reaction. Common chiral ligands include bisphosphine ligands (such as BINAP, DPPF), oxazoline-phosphine ligands, bisoxazoline ligands (such as Box), phosphine-sulfur ligands, etc. These ligands show excellent performance in a variety of asymmetric catalytic reactions, such as asymmetric hydrogenation, Michael addition, asymmetric cycloaddition, asymmetric olefin metathesis, etc.
[0003] It is particularly worth mentioning that Liu Xinyuan's research group synthesized a N, O, P tridentate chiral ligand based on a benzene ring skeleton. This ligand exhibits excellent chemical selectivity and enantioselectivity in CX bonding reactions involving free radicals. Specifically, this type of ligand can effectively stabilize the transition state through its unique three-dimensional structure and electronic effect, thereby improving the selectivity of the reaction. In addition, these ligands have shown good versatility and stability in a variety of reaction systems, further expanding their scope of application.
[0004] Although the types and numbers of chiral ligands are already very rich, each skeleton of the ligand has unique properties and catalytic characteristics. Therefore, the development of new chiral ligands is still of great significance. Especially in the field of N, O, P tridentate chiral ligands, there are few related reports, and existing research mainly focuses on a few specific structures. Therefore, the development of N, O, P tridentate chiral ligands with new skeletons will not only help fill the gap in this field, but also provide more options and possibilities for asymmetric catalysis. This will be of great significance to promote the development of asymmetric catalysis, discover new efficient catalysts, and solve the limitations of existing catalysts.
[0005] In conclusion, with the continuous progress in the field of asymmetric catalysis, the development of new chiral ligands will continue to be one of the research focuses. In particular, the research on N, O, P tridentate chiral ligands is expected to provide new ideas and solutions for future asymmetric catalytic reactions. Summary of the invention
[0006] 1. Technical issues to be resolved
[0007] The purpose of the present invention is to provide a N, P, O tridentate chiral ligand based on a ferrocene skeleton.
[0008] (II) Technical solution
[0009] A N, P, O tridentate chiral ligand based on a ferrocene skeleton is a compound having the following general formula I or an enantiomer, racemate or diastereoisomer of the compound:
[0010]
[0011] In the formula: R is methyl, ethyl, isopropyl, tert-butyl, benzyl, cyclohexyl, isobutyl or phenyl; Ar is phenyl, p-tolyl, p-methoxyphenyl, p-tert-butylphenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-diisopropylphenyl, 3,5-ditrifluoromethylphenyl or 2,6-dimethylphenyl.
[0012] Further, the compound as shown in general formula I is selected from any of the following compounds:
[0013]
[0014] In each formula: R is methyl, ethyl, isopropyl, tert-butyl, benzyl, cyclohexyl, isobutyl or phenyl; Ar is phenyl, p-tolyl, p-methoxyphenyl, p-tert-butylphenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-diisopropylphenyl, 3,5-ditrifluoromethylphenyl or 2,6-dimethylphenyl.
[0015] Further, the compound as shown in general formula I is selected from any one of target compounds 1 to 3:
[0016]
[0017] Furthermore, the preparation method of the target compound 1 is:
[0018] S1: Add TMEDA and methyl tert-butyl ether to [(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]ferrocene under argon atmosphere;
[0019] S2: n-Butyl lithium was added dropwise in a dry ice bath, and then reacted at -78°C for 30 min, and then in an ice bath for 60 min;
[0020] S3: Add TsN3 dropwise, and after the addition, the temperature rises to room temperature naturally, and the reaction is completed;
[0021] S4: After the reaction is completed, water is added to quench, ethyl acetate is added to extract, and the mixture is dried over anhydrous sodium sulfate. After being dried by a rotary evaporator, the mixture is purified by column chromatography using ethyl acetate and petroleum ether;
[0022] S5: adding ethanol to the product obtained in step S4, and adding Pd / C under argon atmosphere;
[0023] S6: After the reaction is completed, the reaction mixture is filtered using diatomaceous earth, and the filter cake is washed with DMC;
[0024] S7: The filtrate was dried by rotary evaporation, and then purified by ethyl acetate and petroleum ether column chromatography to obtain the target compound 1;
[0025] The synthetic route is as follows:
[0026]
[0027] Furthermore, the preparation method of the target compound 2 is:
[0028] S1: (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline was added with DCM, 2-diphenylphosphinobenzoic acid, EDCI and DMAP under argon atmosphere;
[0029] S2: Stirring at room temperature until the reaction is complete;
[0030] S3: After drying by rotary evaporator, purification was performed by ethyl acetate and petroleum ether column chromatography to obtain the target compound II;
[0031] The synthetic route is as follows:
[0032]
[0033] Furthermore, the preparation method of target compound three is:
[0034] S1: (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline was added with DCM, 2-bis(3,5-di-tert-butylphenylphosphino)benzoic acid, EDCI and DMAP under argon atmosphere;
[0035] S2: Stirring at room temperature until the reaction is complete;
[0036] S3: After drying by rotary evaporator, purification was performed by ethyl acetate and petroleum ether column chromatography to obtain the target compound 3;
[0037] The synthetic route is as follows:
[0038]
[0039] (III) Beneficial effects
[0040] The N, P, O tridentate chiral ligand based on the ferrocene skeleton exhibits excellent enantioselectivity and diastereoselectivity in the Sonogashira coupling reaction. This chiral ligand can effectively control the stereochemistry of the reaction, significantly improve the optical purity of the product, and has excellent reaction yield.
[0041] It should be understood that within the scope of the present invention, the above-mentioned various technical features of the present invention and the various technical features specifically described in the following embodiments can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS
[0042] Figure 1 is the NMR spectrum of target compound 1 in the embodiment of the present invention;
[0043] Figure 2 is the NMR spectrum of target compound 2 in the embodiment of the present invention;
[0044] Figure 3 It is the NMR spectrum of target compound three in the embodiment of the present invention. DETAILED DESCRIPTION
[0045] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0046] An N, P, O tridentate chiral ligand based on a ferrocene skeleton provided in an embodiment of the present invention is a compound having the following general formula I or an enantiomer, racemate or diastereomer of the compound:
[0047]
[0048] In the formula: R is methyl, ethyl, isopropyl, tert-butyl, benzyl, cyclohexyl, isobutyl or phenyl; Ar is phenyl, p-tolyl, p-methoxyphenyl, p-tert-butylphenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-diisopropylphenyl, 3,5-ditrifluoromethylphenyl or 2,6-dimethylphenyl.
[0049] The compound represented by general formula I is selected from any of the following compounds:
[0050]
[0051] In each formula: R is methyl, ethyl, isopropyl, tert-butyl, benzyl, cyclohexyl, isobutyl or phenyl; Ar is phenyl, p-tolyl, p-methoxyphenyl, p-tert-butylphenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-diisopropylphenyl, 3,5-ditrifluoromethylphenyl or 2,6-dimethylphenyl.
[0052] The compound represented by general formula I is selected from any one of target compounds 1 to 3:
[0053]
[0054] Note on general reaction conditions: All reactions and controls were performed in an argon-filled glove box or using standard Schlenk techniques when air-sensitive reagents were used. Reaction solvents were dried using general standard procedures.
[0055] In an optional embodiment, the name of the target compound 1 is: (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline, and the preparation method is:
[0056] S1: 5 g, 16 mmol of [(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]ferrocene is placed in a round-bottom flask, and the flask is evacuated and ventilated. Under an argon atmosphere, 5 ml, 24 mmol of TMEDA and methyl tert-butyl ether are added; wherein the methyl tert-butyl ether is anhydrous methyl tert-butyl ether.
[0057] S2: Add 10 ml, 24 mmol of n-butyl lithium dropwise in a dry ice bath, react at -78 °C for 30 min, and react in an ice bath for 60 min;
[0058] S3: Add 10 ml, 48 mmol of TsN3 dropwise, and warm to room temperature naturally after the addition, and react until completion;
[0059] S4: After the reaction is completed, water is added to quench, and ethyl acetate is added to extract, and the mixture is dried over anhydrous sodium sulfate. After being dried by rotary evaporator, the mixture is purified by column chromatography with ethyl acetate and petroleum ether; a yellow solid is obtained with a yield of 77%.
[0060] S5: 3.78 g, 11 mmol of the product obtained in step S4 was placed in a round-bottom flask, ethanol was added, and Pd / C was added under argon atmosphere; hydrogen was replaced three times, and the round-bottom flask was placed in an oil bath (50° C.) and stirred until the reaction was completed.
[0061] S6: After the reaction is completed, the reaction mixture is filtered using diatomaceous earth, and the filter cake is washed with DMC;
[0062] S7: The filtrate was dried by rotary evaporation, and then purified by ethyl acetate and petroleum ether column chromatography to obtain a yellow solid with a yield of 74%, and the target compound 1 was obtained;
[0063] The NMR spectrum of target compound 1 is as follows Figure 1As shown, nuclear magnetic data: 1H NMR (CDCl3, 400MHz) δ = 4.34-4.32 (m, 1H), 4.25-4.11 (m, 3H), 4.06 (s, 5H), 3.96-3.91 (m, 4H), 1.00 (s, 9H)
[0064] The synthetic route is as follows:
[0065]
[0066] In another optional embodiment, the name of the target compound II is (4S)-tert-butyl-(2Sp)-[2-(2-(diphenylphosphinothiocarboxamido)ferrocenyl]-2-oxazoline, and the preparation method is:
[0067] S1: Put 1.76 g, 5.36 mmol of (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline into a round-bottom flask, evacuate the air, and add DCM, 3.29 g, 10.73 mmol of 2-diphenylphosphinobenzoic acid, 2.06 g, 10.73 mmol of EDCI and 1.31 g, 10.73 mmol of DMAP under argon atmosphere; DCM is selected as anhydrous DCM.
[0068] S2: Stirring at room temperature until the reaction is complete;
[0069] S3: After drying by rotary evaporator, ethyl acetate and petroleum ether column chromatography were used to purify the yellow solid with a yield of 73% to obtain the target compound II; the NMR spectrum of the target compound II is as follows Figure 2 As shown, the nuclear magnetic data 1H NMR (CDCl3, 400MHz) δ = 10.41 (br, 1H), 7.78-7.74 (m, 1H), 7.38-7.29 (m, 12H), 7.04-6.99 (m, 1H), 5.56-5.54 (m, 1H), 4.41-4.39 (m, 1H), 4.29-4.24 (m, 1H), 4.20-4.12 (m, 2H), 4.95 (s, 5H), 3.94-3.89 (m, 1H), 0.96 (s, 9H).
[0070] The synthetic route is as follows:
[0071]
[0072] The name of target compound 3: (4S)-tert-butyl-(2Sp)-[2-(2-(di-(3,5-di-tert-butylphenyl)benzamido))ferrocenyl]-2-oxazoline, the preparation method is:
[0073] S1: 1 g, 3.05 mmol of (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline was placed in a round-bottom flask, and the mixture was ventilated. DCM, 3.24 g, 6.10 mmol of 2-bis(3,5-di-tert-butylphenylphosphino)benzoic acid, 1.17 g, 6.10 mmol of EDCI, and 0.74 g, 6.10 mmol of DMAP were added under argon atmosphere;
[0074] S2: Stirring at room temperature until the reaction is complete;
[0075] S3: After drying by rotary evaporator, ethyl acetate and petroleum ether column chromatography were used to purify the yellow solid with a yield of 71% to obtain the target compound 3; the NMR spectrum of the target compound 3 is as follows Figure 3 As shown, nuclear magnetic data: 1H NMR (CDCl3, 400MHz) δ = 10.25 (br, 1H), 7.75-7.71 (m, 1H), 7.35-7.26 (m, 4H), 7.19-7.15 (m, 2H), 7.09-7.06 (m, 2H), 7.01-6.96 (m, 2H), 5.56-5.54 (m, 1H), 4.38-4.36 (m, 1H), 4.27-4.22 (m, 1H), 4.17-4.12 (m, 1H), 4.10-4.09 (m, 1H), 4.02 (s, 5H), 3.92-3.86 (m, 1H), 1.22 (s, 18H), 1.18 (s, 18H), 0.97 (s, 9H)
[0076] The synthetic route is as follows:
[0077]
[0078] Example 1: Weigh 0.015 mmol, 15 mol% of the target compound II and 0.01 mmol, 10 mol% of cuprous iodide;
[0079] The above compounds were placed in a reaction bottle and evacuated three times to make it an argon atmosphere;
[0080] Add 1.0 mL of anhydrous dichloromethane and stir for 30 min;
[0081] Add 0.15 mmol, 1.5 equiv. of phenylacetylene and 0.15 mmol, 1.5 equiv. of cesium carbonate;
[0082] Add (bromo(phenyl)methyl)trimethylsilane;
[0083] The mixture was stirred at room temperature until the reaction was complete (monitored by TLC).
[0084] After the reaction was complete, the solvent was dried by spin drying and the residue was separated by column chromatography using petroleum ether and ethyl acetate.
[0085] (R)-(1,3-diphenylprop-2-en-1-yl)trimethylsilane was obtained in 82% yield and the enantioselective excess was 93% ee as determined by chiral liquid chromatography.
[0086] Example 2: Weigh 0.015 mmol, 15 mol% of the target compound III and 0.01 mmol, 10 mol% of cuprous iodide;
[0087] The above compounds were placed in a reaction bottle and evacuated three times to make it an argon atmosphere;
[0088] Add 1.0 mL of anhydrous dichloromethane and stir for 30 min;
[0089] Add 0.15 mmol, 1.5 equiv. of phenylacetylene and 0.15 mmol, 1.5 equiv. of cesium carbonate;
[0090] Add (bromo(phenyl)methyl)trimethylsilane;
[0091] Stir at room temperature until the reaction is complete (monitored by TLC thin layer chromatography);
[0092] After the reaction was complete, the solvent was dried by spin drying and the residue was separated by column chromatography using petroleum ether and ethyl acetate.
[0093] (R)-(1,3-diphenylprop-2-en-1-yl)trimethylsilane was obtained in 82% yield and the enantioselective excess was 98% ee as determined by chiral liquid chromatography.
[0094] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprises" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device that includes a series of elements includes not only those elements, but also other elements that are not explicitly listed, or also includes elements that are inherent to such process, method, article or device.
[0095] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that not every embodiment includes only one independent technical solution, and in the absence of a conflict of solutions, the various technical features mentioned in each embodiment can be combined in any manner to form other implementation methods that can be understood by those skilled in the art.
[0096] In addition, without departing from the scope of the present invention, the technical solutions described in the aforementioned embodiments may be modified, or some of the technical features may be replaced by equivalents, without causing the essence of the corresponding technical solutions to depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A N, P, O tridentate chiral ligand based on a ferrocene skeleton, which is a compound having the following general formula I or an enantiomer, racemate or diastereomer of the compound: In the formula: R is methyl, ethyl, isopropyl, tert-butyl, benzyl, cyclohexyl, isobutyl or phenyl; Ar is phenyl, p-tolyl, p-methoxyphenyl, p-tert-butylphenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-diisopropylphenyl, 3,5-ditrifluoromethylphenyl or 2,6-dimethylphenyl.
2. The N, P, O tridentate chiral ligand based on a ferrocene skeleton according to claim 1, characterized in that: The compound represented by general formula I is selected from any of the following compounds: In each formula: R is methyl, ethyl, isopropyl, tert-butyl, benzyl, cyclohexyl, isobutyl or phenyl; Ar is phenyl, p-tolyl, p-methoxyphenyl, p-tert-butylphenyl, p-trifluoromethylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, 3,5-diisopropylphenyl, 3,5-ditrifluoromethylphenyl or 2,6-dimethylphenyl.
3. The N, P, O tridentate chiral ligand based on a ferrocene skeleton according to claim 1, characterized in that: The compound represented by general formula I is selected from any one of target compounds 1 to 3:
4. The N, P, O tridentate chiral ligand based on the ferrocene skeleton as claimed in claim 3, wherein the preparation method of the target compound 1 is: S1: Add TMEDA and methyl tert-butyl ether to [(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]ferrocene under argon atmosphere; S2: n-Butyl lithium was added dropwise in a dry ice bath, and the reaction was continued at -78°C for 30 min, and then in an ice bath for 60 min; S3: Add TsN3 dropwise, and after the addition, the temperature rises to room temperature naturally, and the reaction is completed; S4: After the reaction is completed, water is added to quench, ethyl acetate is added to extract, and the mixture is dried over anhydrous sodium sulfate. After being dried by rotary evaporator, the mixture is purified by column chromatography using ethyl acetate and petroleum ether; S5: adding ethanol to the product obtained in step S4, and adding Pd / C under argon atmosphere; S6: After the reaction is completed, the reaction mixture is filtered using diatomaceous earth, and the filter cake is washed with DMC; S7: The filtrate was dried by rotary evaporation, and then purified by ethyl acetate and petroleum ether column chromatography to obtain the target compound 1; The synthetic route is as follows:
5. The N, P, O tridentate chiral ligand based on the ferrocene skeleton as claimed in claim 3, wherein the preparation method of the target compound 2 is: S1: (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline was added with DCM, 2-diphenylphosphinobenzoic acid, EDCI and DMAP under argon atmosphere; S2: Stirring at room temperature until the reaction is complete; S3: After drying by rotary evaporator, purification was performed by ethyl acetate and petroleum ether column chromatography to obtain the target compound II; The synthetic route is as follows:
6. The N, P, O tridentate chiral ligand based on the ferrocene skeleton as claimed in claim 3, wherein the preparation method of the target compound three is: S1: (4S)-tert-butyl-(2Sp)-[2-aminoferrocenyl]-2-oxazoline was added with DCM, 2-bis(3,5-di-tert-butylphenylphosphino)benzoic acid, EDCI and DMAP under argon atmosphere; S2: Stirring at room temperature until the reaction is complete; S3: After drying by rotary evaporator, purify by ethyl acetate and petroleum ether column chromatography to obtain target compound 3; The synthetic route is as follows: