A phosphinamide structure tridentate p,n,n-ligand and its preparation method and application

Abstract

The application provides a preparation method of a novel tridentate P, N, N-ligand with a phosphinamide structure and application thereof in asymmetric catalytic reaction. The chiral ligand is prepared from a pyridine imine compound derived from a chiral binaphthyl diamine and an aryl chlorophosphine as raw materials under the action of a base additive through one-step reaction under mild conditions. The chiral ligand is stable in property, is not sensitive to air and humidity, and can be stored for a long time. The catalyst composed of the tridentate P, N, N-ligand and a Ru metal precursor shows excellent catalytic activity and stereoselectivity in asymmetric hydrogenation reaction.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to a method for preparing a tridentate P,N,N-ligand with a phosphonamide structure and its application in Ru-catalyzed asymmetric hydrogenation reaction. Background Technology

[0002] Catalytic asymmetric hydrogenation of unsaturated double bonds is an important means of obtaining chiral compounds, and chiral ligands are the key to achieving high reactivity and enantioselectivity.

[0003] In 1998, Noyori first utilized chiral diphosphine / diamine with ruthenium to prepare chiral ruthenium-based complexes, achieving highly reactive and enantioselective asymmetric hydrogenation of ketones [(a)Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.; England, AF; Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. 1998, 37, 1703-1707.]. Since then, ruthenium-catalyzed asymmetric hydrogenation has attracted widespread attention. A series of novel ruthenium-based complexes formed by the complexation of chiral ligands with ruthenium have been reported, exhibiting good catalytic performance [(b) Zotto, AD; Baratta, W.; Ballico, M.; Herdtweck, E.; Rigo, P. Organometallics 2007, 26, 5636-5642. (c) Touge, T.; Arai, T. J. A. M. Chem. Soc. 2016, 138, 11299-11305. (d) Che n, , L.; Daniliuc, CG; Mück-Lichtenfeld, C.; Neugebauer, J.; Glorius, FJ Am. Chem. Soc. 2020, 142, 7100-7107].

[0004] Despite significant progress in Ru-catalyzed asymmetric hydrogenation, many challenges remain. Asymmetric hydrogenation reactions of numerous substrates still exhibit low activity, poor enantioselectivity, and most require large amounts of base additives. Therefore, developing novel ligands for Ru-catalyzed asymmetric hydrogenation remains crucial. To this end, we developed a tridentate P,N,N-ligand with a phosphonamide structure and successfully applied it in Ru-catalyzed asymmetric hydrogenation. Summary of the Invention

[0005] The purpose of this invention is to provide a novel tridentate P,N,N-ligand with a phosphonamide structure. This chiral ligand can be used for Ru-catalyzed asymmetric hydrogenation reactions, and the NH bond contained in the ligand plays an important role in the activity and selectivity of the catalyst.

[0006] Specifically, the tridentate P,N,N-ligand of the phosphonamide structure described in this invention has the structure shown in Formula I;

[0007]

[0008] Where Ar is a phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, or 2,4,6-trisubstituted aryl group, etc., with C6-C carbons on the aromatic ring. 60 (preferably C6-C) 30 More preferably C6-C 24 The aromatic group; the substituent is C1-C 40 (preferably C1-C) 30 More preferably, it is a C1-C6 alkane group, C1-C 40 (preferably C1-C) 30 More preferably, it is one or more of (C1-C6) alkoxy, halogen, nitro, ester or cyano groups;

[0009] R, R 1 They can be the same or different groups, and can be hydrogen or C1-C. 40 (preferably C1-C) 30 More preferably, it is a C1-C6 alkane group; the number of carbons on the aromatic ring is C6-C6. 60 (preferably C6-C) 30 More preferably C6-C 24 The aromatic group, the aromatic ring containing one or more N, S, O, P heteroatoms, the aromatic ring having C3-C4 carbon atoms. 60 Aromatic groups (preferably C3-C) 30 More preferably C3-C 24 ).

[0010] To achieve the above objectives, in this invention, the preparation method of the tridentate P,N,N-ligand I with the phosphonamide structure is carried out according to the following reaction route.

[0011]

[0012] In this invention, the preparation method of the tridentate P,N,N-ligand I with the phosphonamide structure includes the following steps:

[0013] Under nitrogen protection, a solution containing diarylphosphine chloride III was slowly added dropwise at low temperature with stirring to a solution containing a chiral binaphthyldiamine-derived pyridineimine compound II and a base. TCL analysis showed that the reactants were almost completely consumed. The reaction solution was concentrated under reduced pressure until almost solvent-free, separated by silica gel column chromatography, concentrated under reduced pressure, and dried under vacuum to obtain a tridentate P,N,N-ligand with a phosphonamide structure.

[0014] In this invention, the reaction medium is selected from one or more aprotic solvents, such as tetrahydrofuran, diethyl ether, ethyl acetate, toluene, and dichloromethane. Dichloromethane is preferred.

[0015] The alkaline additive is selected from... i Pr2NEt、 i PrNMe2, NEt3, DMAP, KOH, NaOH, Na2CO3, Cs2CO3, K2CO3, NaHCO3, t BuOK t BuONa t One or more of BuOLi, MeONa, or K3PO4; preferably NET3.

[0016] The molar ratio of the chiral binaphthyldiamine-derived pyridineimine compound II to diarylphosphine chloride III is 1:0.5-1:2.5. Preferably, it is 1:2.0-1:2.5; more preferably, it is 1:2.2.

[0017] The molar ratio of the chiral binaphthyldiamine-derived pyridineimide compound II to the base additive is 1:1.0-1:3.0. Preferably, it is 1:1.5-1:2.5; more preferably, it is 1:2.2.

[0018] The reaction temperature is -30 to 20°C. Preferably, it is -10 to 10°C; more preferably, it is 0°C.

[0019] In this invention, the tridentate P,N,N-ligand I with the phosphonamide structure has the following advantageous ligand structure:

[0020]

[0021] This invention also relates to the application of the above-mentioned ligands in Ru-catalyzed asymmetric hydrogenation reactions.

[0022] This invention provides a novel tridentate P,N,N-ligand with a phosphonamide structure, which can be used in Ru-catalyzed asymmetric hydrogenation reactions. The Ru metal catalyst precursor is selected from (PPh3)2Ru(CO)2Cl2, (PPh3)3RuH(CO)Cl, (PPh3)4RuCl2, and [(p-cymene)RuCl2]2. Preferably, it is (PPh3)3RuH(CO)Cl.

[0023] The beneficial effects of this invention are:

[0024] The tridentate P,N,N-ligands with phosphonamide structure described in this invention have the advantages of simple preparation method, stable properties, insensitivity to air and humidity, and easy structural modification. They exhibit good reactivity and enantioselectivity in Ru-catalyzed asymmetric hydrogenation reactions. Attached Figure Description

[0025] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. Hereinafter, embodiments of the invention will be described in detail with reference to the accompanying drawings, wherein:

[0026] Figure 1 The chiral tridentate P,N,N-ligand (S) prepared in Example 1 a )-I-1a proton spectrum;

[0027] Figure 2 The chiral tridentate P,N,N-ligand (S) prepared in Example 1 a )-I-1a phosphorus spectrum; Detailed Implementation

[0028] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods or product instructions. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only. The nuclear magnetic resonance (NMR) measurements in this embodiment of the invention were performed using a Bruker 400 NMR spectrometer.

[0030] Example 1

[0031] Pyridineimide compounds derived from chiral binaphthyldiamine (S a Tridentate P,N,N-ligands with phosphonophosphorus chloride III-1a (Yuan, Z.; Lei, Z.; Shi, M. Tetrahedron: Asymmetry 2008, 19, 1339-1346.) were prepared from diphenylphosphonophosphorus chloride III-1a as a raw material to prepare tridentate P,N,N-ligands with phosphonophosphorus chloride III-1a. a )-I-1a.

[0032]

[0033] Under nitrogen protection, chiral (S) gas was added to the reaction flask. a )-Pyridylimine compounds derived from naphthyldiamine (S a Add 1.0 mmol, 1.0 equiv of diphenylphosphine chloride III-1a (DCM) to 5.0 mL of anhydrous dichloromethane (DCM) and 2.2 mmol, 2.2 equiv of Et3N, and stir the reaction mixture at 0 °C. Then, add 5.0 mL of anhydrous DCM solution of 2.2 mmol, 2.2 equiv of diphenylphosphine chloride III-1a dropwise to the reaction mixture and stir at 0 °C for 12 h. After the reaction is complete as determined by TCL, add 20.0 mL of water, separate the organic layer, extract the aqueous layer with DCM (10.0 mL x 2), combine the organic layers, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure until substantially solvent-free, separate by silica gel column chromatography, concentrate under reduced pressure, and dry under vacuum to obtain a yellow solid (S). a )-I-1a 479.8mg, 86% yield.

[0034] Product (S) a I-1a was determined by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. 1 H NMR (400MHz, CDCl3) δ7.91-6.95 (m, 25H), 4.62 (d, J = 7.6Hz, 1H). 31 P NMR (162MHz, CDCl3): δ27.1; HRMS cal.forC 38 H 29 N3P + [M+H] + :558.2094,found:558.2092.

[0035] Example 2

[0036] The solvent DCM in Example 1 was replaced with an equal volume of toluene, and the other conditions and procedures were the same as in Example 1. A yellow solid (S) was obtained. a )-I-1a441.4mg, 79% yield.

[0037] Example 3

[0038] Replace the equimolar amount of Et3N in Example 1 with K2CO3, and keep the other conditions and procedures the same as in Example 1. A yellow solid (S) is obtained. a )-I-1a 408.4mg, 73% yield.

[0039] Example 4

[0040] Replace Et3N (2.2 mmol, 2.2 equiv.) in Example 1 with Et3N (1.2 mmol, 1.2 equiv.), and follow the same conditions and procedures as in Example 1. A yellow solid (S) is obtained. a )-I-1a340.4mg, 61% yield.

[0041] Example 5

[0042] The reaction temperature in Example 1 was increased from 0°C to 20°C, while the remaining conditions and procedures were the same as in Example 1. A yellow solid (S) was obtained. a )-I-1a 451.9mg, 81% yield.

[0043] Example 6

[0044]

[0045] The tridentate P,N,N-ligand (S) with a phosphonamide structure a A solution of 1 mL of THF containing 0.0011 equiv., 0.0022 mmol, 1.2 mg of phenylethyl ethane (PPH3)4RuCl2 (PPh ...)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2)4RuCl2 (PPh3)4RuCl2 (PPh3)4RuCl2)4RuCl2 (PPh3)4RuCl2 (

[0046] Example 7

[0047] The tridentate P,N,N-ligand (S) with the phosphamide structure from Example 6 was used. a Replace )-I-1a (0.0011 equiv., 0.0022 mmol, 1.2 mg) with (S a (S)-I-1a (0.0022 equiv., 0.0044 mmol, 2.4 mg), with the remaining conditions and procedures the same as in Example 6. The product (S)-1-phenylethane-1-ol was obtained with 99% yield and 91% ee enantioselectivity.

[0048] Example 8

[0049] In Example 6, the equimolar amount of (PPh3)4RuCl2 was replaced with (PPh3)3RuH(CO)Cl, and the remaining conditions and procedures were the same as in Example 6. The product (S)-1-phenylethane-1-ol was obtained with 99% yield and 99% ee enantioselectivity.

[0050] Example 9

[0051] The tridentate P,N,N-ligand (S) with a phosphonamide structure a (S)-1-phenylethane-1-ol was stored in air for seven days before use, and the rest was the same as in Example 8. The product (S)-1-phenylethane-1-ol was still obtained with 99% yield and 99% ee enantioselectivity. The ligand catalytic activity remained unchanged.

Claims

1. A tridentate P,N,N-ligand with a phosphonamide structure, characterized in that, It has the structure shown in the following formula: Where Ar is a phenyl group; R is hydrogen, R 1 It is a hydrogen or C1-C6 alkane group.

2. The tridentate P,N,N-ligand with a phosphonamide structure according to claim 1, characterized in that, Its ligand structure is as follows: 。 3. The method for preparing the tridentate P,N,N-ligand with a phosphonamide structure according to claim 1 or 2, characterized in that, The preparation route is as follows: ； Among them, Ar, R, R 1 The Ar, R, and R in claim 1 or 2 respectively 1 .

4. The preparation method according to claim 3, characterized in that, The preparation route includes the following specific steps: Under nitrogen protection, a solution containing diarylphosphine chloride III dissolved in the reaction medium was added dropwise with stirring to a solution containing a chiral binaphthyldiamine-derived pyridineimine compound II and a base additive dissolved in the reaction medium. The reaction was stopped when either of the two reactants was completely consumed by TCL detection. The reaction solution was concentrated under reduced pressure, separated by silica gel column chromatography, concentrated under reduced pressure, and dried to obtain a tridentate P,N,N-ligand with a phosphonamide structure.

5. The method according to claim 4, characterized in that, The reaction medium is selected from one or more of tetrahydrofuran, diethyl ether, ethyl acetate, toluene, and dichloromethane.

6. The method according to claim 4, characterized in that, The alkaline additive is selected from... i Pr2NEt、 i PrNMe2, NEt3, DMAP, KOH, NaOH, Na2CO3, Cs2CO3, K2CO3, NaHCO3, t BuOK t BuONa t One or more of BuOLi or MeONa.

7. The method according to claim 4, characterized in that, The molar ratio of chiral binaphthyldiamine-derived pyridineimine compound II to diarylphosphine chloride III is 1:0.5-2.5; The molar ratio of chiral binaphthyldiamine-derived pyridineimine compound II to base additive is 1:1.0-3.

0.

8. The method according to claim 4, characterized in that, The reaction temperature is -30 to 20. o C.

9. The application of a tridentate P,N,N-ligand with a phosphonamide structure as described in claim 1 or 2, characterized in that, The catalyst composed of the tridentate P,N,N-ligand with the phosphonamide structure and the ruthenium metal precursor is used to catalyze the asymmetric catalytic hydrogenation of ketone compounds.

10. The application according to claim 9, characterized in that, The ruthenium metal precursor is one or more of (PPh3)2Ru(CO)2Cl2, (PPh3)3RuH(CO)Cl, (PPh3)4RuCl2, and [(p-cymene)RuCl2]2; The molar ratio of ruthenium metal precursor to tridentate P,N,N-ligands with phosphonamide structure is 1:1.1-3.3.

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