Method for hydrogenation kinetic resolution or dynamic kinetic resolution of lactone under catalysis of palladium
The palladium catalytic system uses palladium and chiral bisphosphine ligand to catalyze the hydrogenation kinetic or dynamic kinetic resolution of lactone, which solves the safety and environmental pollution problems of existing ester reduction methods, and achieves efficient and specific product generation and enantioselectivity.
Patent Information
- Application Number
- CN202311263865.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-27
- Publication Date
- 2025-03-28
AI Technical Summary
The existing ester reduction methods have problems such as expensive, unsafe operation, many by-products, and environmental pollution. The palladium catalytic system has not yet been studied in the hydrogenation kinetic or dynamic kinetic resolution of ester functional groups.
Palladium and chiral bisphosphine ligands are used as catalysts to achieve hydrogenation kinetic or dynamic kinetic split of lactone by exohydrogenation. The reaction conditions are mild and the operation is simple.
It achieves high reaction activity and enantioselectivity, specialized products, few side reactions, easy separation, high enantiomer pure products, stable catalyst and simple operation.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a homogeneous system using palladium to carry out hydrogenation kinetic resolution or dynamic kinetic resolution on a lactone substrate. Background Art
[0002] The reduction of carboxylic acid esters to alcohols is a very important type of organic chemical reaction. It has a wide range of uses in organic synthesis and has been applied to the production of fine chemicals such as medicines, pesticides, and spices. Traditional reduction methods for esters mainly use negative hydrogen reagents such as lithium aluminum hydride, metal borohydrides, and borane. In addition to the disadvantages of high prices and unsafe operation, these methods often require the consumption of equivalent or several times the equivalent of alkali for treatment, which will produce a large number of by-products, resulting in troublesome post-treatment and pollution to the environment. Homogeneous catalytic hydrogenation is a reduction method with high atom economy, simple operation, and environmental friendliness. It has been widely used in the production of medicines, pesticides, spices, etc. Through the continuous efforts of chemists, the asymmetric hydrogenation reaction of esters has developed rapidly, for example: (a) de Vries, JG; Elsevier, CJ Eds The Handbook of Homogeneous Hydrogenation, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007. (b) Zhang, L.; Han, Z.; Zhang, L.; Li, M.; Ding, K. Chin. J. Org. Chem. 2016, 36, 1824. (c) Li, Y.; Wang, Z.; Liu, Q. Chin. J. Org. Chem. 2017, 37, 1978. (d) Chen, S.; Yang, W.; Yao, Y.; Yang, X.; Deng, Y.; Yang, D. Chin. J. Org. Chem. 2018, 38, 2534.
[0003] In the past decade, the asymmetric hydrogenation of racemic esters to prepare the corresponding chiral primary alcohols has been widely studied. The research groups of Ikariya, Zhou Qilin, Ohkuma, Zhang Xumu, and Bergens used ruthenium and iridium catalytic systems to efficiently achieve the hydrogenation kinetic resolution and dynamic kinetic resolution of racemic esters, and obtained a series of chiral primary alcohols, such as: (a) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi, A.; Himizu, A.; Ikariya, T. Am. Chem. So c.2011,133,4240.(b)Liu,C.;Xie,J.-H.;Li,Y.-L.;Chen,J.-Q.;Zhou,Q.-L.Angew.Chem.Int.Ed.2013,52,5 93. (c) Yang, X.-H.; Xie, J.-H.; Liu, W.-P.; Zhou, Q.-L. a, T.; Kawaguchi, K.; Masumoto, Y.; Ohkuma, T. Angew. Chem. Int. Ed. 2018, 57, 1386. (e) Yang, X.-H.; Wang, K.; Z hu, S.-F.; Xie, J.-H.; Zhou, Q.-LJAm.Chem.Soc.2014,136,17426.(f) Yang, .; n, Q.-S.; Jia, S.-P.; Yin, Q.; Zhang, Catal.2019,9,6111.(i)Gu,X.-S.;Yu,N.;Yang,X.-H.Zhu,A.-T.;Xie,J.-H.;Zhou,Q.-L.Org.Lett.2019,21,4111.)
[0004] However, there are currently no reports on the related research on the hydrogenation kinetic resolution or dynamic kinetic resolution of ester functional groups using a palladium catalytic system. Research and development of a palladium-catalyzed hydrogenation kinetic resolution or dynamic kinetic resolution method for lactones will greatly enrich the methods for homogeneous asymmetric catalytic hydrogenation of lactones. Summary of the invention
[0005] The object of the present invention is to provide a method for palladium-catalyzed lactone hydrogenation kinetic resolution or dynamic kinetic resolution. Based on our previous research on palladium-catalyzed hydrogenation systems, the palladium-catalyzed system can realize asymmetric hydrogenation of compounds such as imines, enamines, and alkenes, and has good functional group compatibility, and the coordination number of palladium is 4, and other components of the reaction are not easy to coordinate with the catalyst, and have good stability. In addition, the palladium-catalyzed hydrogenation system is an acidic system, which can activate the C=O bond and has potential hydrogenation activity for the C=O bond of the ester group.
[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:
[0007] The present invention provides a method for hydrogenation kinetic resolution or dynamic kinetic resolution of lactone catalyzed by palladium, wherein palladium and a chiral diphosphine ligand are used as catalysts, and hydrogenation kinetic resolution or dynamic kinetic resolution of lactone is achieved by adding hydrogen gas. The reaction formula is as follows:
[0008]
[0009] Where: R is C1-C 20 An alkyl group, a benzyl group, a phenyl group or an aromatic ring containing a substituent; the substituent is at least one of an electron withdrawing group or an electron donating group;
[0010] Ar is a phenyl group or a benzene ring containing a substituent; the substituent is at least one of an electron withdrawing group or an electron donating group;
[0011] Alkyl is C1-C 12 An alkyl group, an alkoxy group or a benzyl group containing a substituent; the substituent is at least one of an electron withdrawing group and an electron donating group.
[0012] Based on the above technical scheme, preferably, the electron withdrawing group or the electron donating group includes methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyano and halogen.
[0013] Based on the above technical scheme, preferably, the metal precursor of palladium is palladium acetate, palladium trifluoroacetate, palladium chloride, bis(benzylideneacetone)palladium, palladium acetylacetonate, dicyanopalladium dichloride, bis(tri-tert-butylpalladium), or tetrakistriphenylphosphine palladium.
[0014] Based on the above technical scheme, preferably, the chiral bisphosphine ligand is one of (R)-SynPhos, (R)-SegPhos, (S,S',R,R')-DuanPhos, (R,R)-Quinoxp*, (S,S)-Me-DuPhos, (S,S)-Ph-BPE, (R,R)-Quinoxp*.
[0015] Based on the above technical solution, preferably, the method comprises the following steps:
[0016] (1) adding a palladium metal precursor and a chiral diphosphine ligand into a reaction container, replacing the air with an inert gas, adding acetone, stirring for 0.5 to 5 hours, and then removing the acetone to obtain a catalyst;
[0017] (2) Under an inert gas atmosphere, a solvent is added to the reaction vessel containing the catalyst in step (1), and then the obtained catalyst solution is transferred to a reaction kettle pre-filled with a reaction substrate (lactone). After sealing, hydrogen is introduced at a pressure of 100 to 1000 psi, and the reaction is carried out at 0 to 80° C. for 15 to 120 hours. The chiral alcohol or the lactone compound containing a quaternary carbon chiral center and the enantiochiral alcohol are obtained by column chromatography separation.
[0018] Based on the above technical solution, preferably, the molar ratio of the palladium metal precursor and the chiral diphosphine ligand in step (1) is 1:1 to 1:2.
[0019] Based on the above technical solution, preferably, the chiral bisphosphine ligand in step (1) is (R,R)-TMS-QuinoxP*.
[0020] Based on the above technical solution, preferably, the inert gas described in step (1) and step (2) includes nitrogen, argon and helium.
[0021] Based on the above technical solution, preferably, the solvent in step (2) includes one or a mixed solution of two or more of 2,2,2-trifluoroethanol, dichlorohexane, hexafluoroisopropanol, and toluene.
[0022] Based on the above technical solution, preferably, the solvent described in step (2) is hexafluoroisopropanol.
[0023] Based on the above technical solution, preferably, the molar ratio of the palladium metal precursor to the reaction substrate in step (2) is 1:50 to 1:100.
[0024] Based on the above technical solution, preferably, the concentration of the reaction substrate in step (2) is 0.01 to 1.0 mmol / mL.
[0025] Based on the above technical solution, preferably, in step (2), the reaction temperature is 35-45° C., and the hydrogen pressure is 300-600 psi.
[0026] The present invention has the following beneficial effects:
[0027] 1. The method of the present invention has high reaction activity and enantioselectivity, complete reaction, specific product generation, no side reaction detected by nuclear magnetic hydrogen spectrum, convenient separation, and high enantiomeric excess pure product can be obtained.
[0028] 2. The catalyst of the method of the present invention is easy to prepare, and the reaction operation is simple and practical.
[0029] 3. The hydrogenation reaction conditions of the method of the present invention are mild and the reaction can be carried out at room temperature.
[0030] 4. The chiral quaternary carbon-containing lactone and the corresponding chiral alcohol derivative obtained by the present invention can be further derivatized. DETAILED DESCRIPTION
[0031] The present invention is described in detail below by examples, but the present invention is not limited to the following examples. DETAILED DESCRIPTION
[0033] The present invention is described in detail below by way of examples, but the present invention is not limited to the following examples. The catalyst used in the present invention is a bisphosphine complex of palladium, which is synthesized according to known literature (Iwamoto, H.; Ozawa, Y.; Takenouchi, Y.; Imamoto, T.; Ito, HJAm. Chem. Soc. 2021, 143, 6413.); lactone is synthesized according to the literature method ((a) Sharma, KR; Singh, V.; Tiwari, N.; Butcher, RJ; Katiyar, D. Bioorg. Chem. 2020, 98, 103700. (b) S.; Pietruszka, J. Adv. Synth. Catal. 2014, 356, 1007.)
[0034] Examples 1-13
[0035] The palladium-catalyzed hydrogenation of lactones was used to dynamically resolve lactone 1a to synthesize chiral alcohol 2a. The specific process is as follows:
[0036] Palladium trifluoroacetate (0.01 mmol, 3.2 mg) and chiral ligand (0.012 mmol) were placed in a reaction flask, 1 ml of acetone was added after nitrogen substitution, stirred at room temperature for 1 hour, and then concentrated in vacuo. 1 ml of organic solvent was added under nitrogen, and the solution was transferred to a reactor pre-placed with substrate 1a (44.0 mg, 0.2 mmol), and hydrogen was introduced at 400 psi and 40° C. for 48 hours. Hydrogen was slowly released, and the solvent was removed and then directly separated by column chromatography to obtain a pure product. The types of organic solvents and chiral bisphosphine ligands were changed during the reaction process, and the reaction temperature was shown in Table 1. The reaction formula and ligand structure are as follows:
[0037]
[0038] The yield is the conversion rate. The enantiomeric excess of the product is determined by chiral liquid chromatography (Chiralpak AS-H). The type of organic solvent is changed during the process. See Table 1 for details.
[0039] Table 1. Optimization of dynamic kinetic resolution conditions for lactones a
[0040]
[0041]
[0042] Examples 14-25
[0043] Kinetic Resolution of Quaternary Carbon-Containing Lactones by Palladium-Catalyzed Hydrogenation
[0044] Palladium trifluoroacetate (0.015 mmol, 4.8 mg) and chiral ligand (0.018 mmol) were placed in a reaction flask. After nitrogen substitution, 1 ml of acetone was added. The mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. 1 ml of organic solvent was added under nitrogen. The solution was transferred to a reactor containing substrate 3a (96 mg, 0.3 mmol) in advance. Hydrogen was introduced at 400 psi and reacted at 40°C for 48 hours. Hydrogen was slowly released, and then sodium cyanoborohydride was added and stirred for 2 hours to completely convert the hemiacetal product in the system. After removing the solvent, the pure product was directly separated by column chromatography. The types of organic solvent and chiral bisphosphine ligand in the reaction, the reaction temperature, and the specific structure are shown in Table 2. The reaction formula and ligand structure are as follows:
[0045]
[0046] The yield is the isolated yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography.
[0047] Table 2. Optimization of lactone kinetic resolution conditions a
[0048]
[0049]
[0050] Embodiment 26-41
[0051] Dynamic Kinetic Resolution of Palladium-Catalyzed Hydrogenation of Lactones
[0052] Palladium trifluoroacetate (0.01 mmol, 3.2 mg) and chiral ligand (0.012 mmol, 4.0 mg) were placed in a reaction flask. After nitrogen substitution, 1 ml of acetone was added. The mixture was stirred at room temperature for 1 hour, and then concentrated in vacuo. 1 ml of hexafluoroisopropanol / toluene (5:1) organic solvent was added under nitrogen. The solution was transferred to a reactor containing lactone substrate 1 (0.2 mmol) in advance. Hydrogen was introduced at 400 psi and reacted at 30°C for 48 hours. The hydrogen was slowly released. After removing the solvent, the pure product was directly separated by column chromatography. The reaction formula is as follows:
[0053]
[0054] The yield is the separation yield. The enantiomeric excess of the product is determined by chiral liquid chromatography. Different products are obtained by selecting different R groups. The specific product structures, yields and ee values are shown below:
[0055]
[0056] Examples 42-56
[0057] Palladium-catalyzed dynamic kinetic resolution of lactones
[0058] Palladium trifluoroacetate (0.015 mmol, 4.8 mg) and chiral ligand (0.018 mmol) were added to the reaction flask, 1 ml of acetone was added after nitrogen replacement, stirred at room temperature for 1 hour, and then concentrated in vacuo. 1 ml of hexafluoroisopropanol was added under nitrogen, and the solution was transferred to a reactor containing quaternary carbon lactone substrate 3 (0.3 mmol) in advance, and hydrogen was introduced at 400 psi, 40°C for 72 hours, and hydrogen was slowly released. Sodium cyanoborohydride (0.12 mmol, 7.6 mg) was added to the system. After removing the solvent, the pure product was directly separated by column chromatography. The reaction formula is as follows:
[0059]
[0060] The yield of the quaternary carbon chiral center lactone and the corresponding chiral alcohol is the separation yield. The enantiomeric excess of the product is determined by chiral liquid chromatography. Different R groups are selected to obtain different products. The specific product structure, yield and ee value are shown below:
[0061]
[0062] The characterization data of the above compounds are as follows:
[0063]
[0064]
[0065]
[0066]
[0067]
[0068]
[0069]
Claims
1. A method for palladium-catalyzed hydrogenation kinetic resolution or dynamic kinetic resolution of lactones, characterized in that: Using palladium and chiral diphosphine ligand as catalysts, hydrogenation kinetic resolution or dynamic kinetic resolution of lactone is achieved by adding hydrogen. The reaction formula is as follows: Where: R is C1-C 20 An alkyl group, a benzyl group, a phenyl group or an aromatic ring containing a substituent; the substituent is at least one of an electron withdrawing group or an electron donating group; Ar is a phenyl group or a benzene ring containing a substituent; the substituent is at least one of an electron withdrawing group or an electron donating group; Alkyl is C1-C 12 An alkyl group, an alkoxy group or a benzyl group containing a substituent; the substituent is at least one of an electron withdrawing group and an electron donating group.
2. The method according to claim 1, characterized in that The electron withdrawing group or the electron donating group include methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyano and halogen.
3. The method according to claim 1, characterized in that The metal precursor of palladium is palladium acetate, palladium trifluoroacetate, palladium chloride, bis(benzylideneacetone)palladium, palladium acetylacetonate, dicyanopalladium dichloride, bis(tri-tert-butylpalladium), tetrakis(triphenylphosphine)palladium; the chiral bisphosphine ligand is (R)-SynPhos, (R)-SegPhos, (S,S',R,R')-DuanPhos, One of (R,R)-Quinoxp*, (S,S)-Me-DuPhos, (S,S)-Ph-BPE, (R,R)-Quinoxp*.
4. The method according to claim 1, characterized in that The method comprises the following steps: (1) adding a palladium metal precursor and a chiral diphosphine ligand into a reaction container, replacing the air with an inert gas, adding acetone, stirring for 0.5 to 5 hours, and then removing the acetone to obtain a catalyst; (2) Under an inert gas atmosphere, a solvent is added to the reaction vessel containing the catalyst in step (1), and then the obtained catalyst solution is transferred to a reaction kettle pre-filled with a reaction substrate (lactone). After sealing, hydrogen is introduced at a pressure of 100 to 1000 psi, and the reaction is carried out at 0 to 80° C. for 15 to 120 hours. The chiral alcohol or the lactone compound containing a quaternary carbon chiral center and the enantiochiral alcohol are obtained by column chromatography separation.
5. The method according to claim 4, characterized in that In step (1), the molar ratio of the palladium metal precursor to the chiral diphosphine ligand is 1:1 to 1:
2.
6. The method according to claim 4, characterized in that The inert gas described in step (1) and step (2) includes nitrogen, argon and helium.
7. The method according to claim 4, characterized in that The solvent in step (2) includes one or a mixed solution of two or more of 2,2,2-trifluoroethanol, dichlorohexane, hexafluoroisopropanol, and toluene.
8. The method according to claim 4, characterized in that The molar ratio of the palladium metal precursor to the reaction substrate in step (2) is 1:50 to 1:
100.
9. The method according to claim 4, characterized in that The reaction substrate concentration in step (2) is 0.01 to 1.0 mmol / mL.
10. The method according to claim 4, characterized in that In step (2), the reaction temperature is 35-45° C. and the hydrogen pressure is 300-600 psi.