A phosphine-1,2-diphenylethylenediamine ligand of a chiral benzene ring skeleton, a preparation method thereof, and an application thereof

Abstract

The present invention provides a class of novel chiral benzene-ring framework phosphine-1,2-diphenylethylenediamine ligands, their preparation methods, and their applications in asymmetric hydrogenation reactions. 2-Diphenylphosphinobenzaldehyde and 1,2-diphenylethylenediamine are added to a Schlenk flask in a molar ratio of 1:1.2. After filling with nitrogen, methanol (0.2 M) is added. The resulting mixture is refluxed at 80 °C for 1-2 hours. After cooling to room temperature, 2 equiv. of NaBH4 is added, and then the mixture is refluxed again at 80 °C for 3-4 hours. After cooling to room temperature, water is added to the reaction solution, and then extracted with dichloromethane, dried over anhydrous sodium sulfate. After removing the solvent, the desired chiral benzene-ring framework phosphine-1,2-diphenylethylenediamine ligand is obtained by column chromatography. The catalysts formed by the chiral ligands of the present invention and metal precursors such as Ir- and Ru- have excellent catalytic activity and stereoselectivity in the catalytic asymmetric hydrogenation reactions of C=C, C=N, and C=O double bonds, with an enantioselectivity of up to 99% ee and a TON of up to 100,000.

Description

Technical Field

[0001] The present invention relates to a preparation method of a phosphine-1,2-diphenylethylenediamine ligand with a novel chiral benzene ring skeleton. The present invention also relates to the application of the above ligand in the asymmetric hydrogenation reaction of C═C, C═N, and C═O double bonds. Background Art

[0002] The asymmetric hydrogenation of C═O and C═N unsaturated double bonds catalyzed by transition metals is one of the simplest and most effective methods for synthesizing chiral alcohols and amines, which can be used to synthesize bioactive compounds such as drugs, perfumes, and agrochemicals [(a) Rosenblum, S.B.; Huynh, T.; Afonso, A.; Davis, H.R., Jr.; Yumibe, N.; Clader, J.W.; Burnett, D.A. J. Med. Chem. 1998, 41, 973. (b) Wong, D.T.; Robertson, D.W.; Bymaster, F.P.; Krushinski, J.H.; Reid, L.R. Life Sci. 1988, 43, 2049. (c) Nishii, H.; Chiba, T.; Morikami, K.; Fukami, T.A.; Sakamoto, H.; Kwangseok, K.; Koyano, H. Bioorg. Med. Chem. Lett. 2010, 20, 1405.]. In the asymmetric hydrogenation reaction, chiral ligands and central metals play crucial roles. Currently, a series of transition metals such as Ru, Rh, Ir, Pd, Mn, etc. are used as central metals for the asymmetric hydrogenation of C═O and C═N unsaturated double bonds, and the complexes formed by these transition metals and suitable chiral ligands exhibit very high reaction activity, enantioselectivity, and substrate generality.

[0003] In recent years, non-C2 symmetric chiral ligands have made great progress in asymmetric hydrogenation. Among them, non-C2 symmetric chiral ligands containing tridentate P,N,N have received extensive attention due to their extremely high reaction activity and enantioselectivity in asymmetric catalytic hydrogenation reactions. In 2011, Zhou et al. reported a P,N,N tridentate ligand based on spirocyclic pyridine-aminophosphine. The complex formed by this chiral ligand and iridium metal had a TOF as high as 100000 h in the asymmetric hydrogenation of simple and polyfunctional ketones -1, Enantioselectivity ee > 99% [(d) Xie, J.; Liu, X.; Xie, J.; Wang, L.; Zhou, Q. Angew. Chem. Int. Ed. 2011, 50, 7329.]. Subsequently, Zhang, Hu, Farkas, etc. successively reported that P,N,N tridentate ligands based on ferrocene, aromatic rings, and linear alkanes showed good reactivity and selectivity in the asymmetric hydrogenation of ketones or imines [(e) Wu, U.; Xie, Y.; Li, P.; Li, X.; Liu, Y.; Dong, X.; Zhang, X. Org. Lett. 2016, 18, 2938. (f) Qin, C.; Chen, X.; Hou, C.; Liu, H.; Liu, Y.; Huang, D.; Hu, X. Synth. Commun. 2018, 48, 672. (g) Császár, Z.; Szabó, E. Z.; Bényei, A. C.; Bakos, J.; Farkas, G. Catal. Commun. 2020, 146, 2938.]. Nevertheless, there are still huge challenges in the field of asymmetric hydrogenation reactions. First, the stereoselectivity of compounds with small differences in electronic effects and steric hindrance is poor; second, the reactivity and selectivity of cheap metals as the central metal of the complex need to be improved; therefore, the design and synthesis of new chiral ligands P,N,N still have important research significance and application value Summary of the Invention

[0004] The present invention discloses a class of phosphine-1,2-diphenylethylenediamine ligands with a chiral benzene ring skeleton and a preparation method thereof

[0005] To achieve the above object, the phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton provided by the present invention has the following structure:

[0006]

[0007] In the formula:

[0008] Ar is an aromatic group containing or not containing functional groups such as N, S, O, P, etc. within C6-C, such as phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, 2,4,6-trisubstituted aryl 60 inside;

[0009] R 1 、R 2 are the same or different groups, and are hydrogen, aliphatic groups within C1-C 40 inside, aliphatic groups containing one or more N, S, O, P heteroatoms; C7-C 60Combined groups of aromatic groups and aliphatic groups, C3-C containing one or more N, S, O, P heteroatoms 60 Combined groups of aromatic groups and aliphatic groups; C6-C 60 Aromatic groups; or heteroaromatic groups containing one or more N, S, O, P heteroatoms.

[0010] R 1 、R 2 Together form cycloalkyl groups and cycloalkyl-derived groups.

[0011] The phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton, and its dominant absolute configuration is (S,S) or (R,R)

[0012] The phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton, the above C1-C 40 Aliphatic group is preferably methyl I-1c.

[0013]

[0014] The phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton, the above cycloalkyl groups and cycloalkyl-derived groups are preferably heptahydropiperidine rings I-1f.

[0015]

[0016] The present invention provides a preparation method of a phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton: The phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton is synthesized according to the following route:

[0017]

[0018] In the formula:

[0019] Ar is an aromatic group containing or not containing functional groups such as N, S, O, P within C6-C, such as phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, 2,4,6-trisubstituted aryl groups; 60 Inner aromatic groups;

[0020] R is hydrogen, an aliphatic group within C1-C 40 Inner, an aliphatic group containing one or more N, S, O, P heteroatoms, a combined group of an aromatic group and an aliphatic group within C7-C 60 Combined groups of aromatic groups and aliphatic groups, C3-C containing one or more N, S, O, P heteroatoms 60 Combined groups of aromatic groups and aliphatic groups, C6-C 60 Inner aromatic groups, heteroaromatic groups containing one or more N, S, O, P heteroatoms;

[0021] R1 , R 2 are the same or different groups, being hydrogen, a C1-C 40 aliphatic group including those within, an aliphatic group containing one or more N, S, O, P heteroatoms; a C7-C 60 combined group of an aromatic group and an aliphatic group, a C3-C 60 combined group of an aromatic group and an aliphatic group containing one or more N, S, O, P heteroatoms; a C6-C 60 aromatic group; or a heteroaromatic group containing one or more N, S, O, P heteroatoms.

[0022] R 1 , R 2 together form a cycloalkyl group and a cycloalkyl-derived group.

[0023] Under a nitrogen atmosphere, 5 mL of a methanol solution (0.2 M) was added to a Schlenk flask containing 2-diphenylphosphinobenzaldehyde and 1,2-diphenylethylenediamine. The resulting mixture was reacted at 80 °C for 1 hour. After cooling to room temperature, 2 equiv. of NaBH4 was added. Subsequently, it was reacted again at 80 °C for 3 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with dichloromethane and drying with anhydrous sodium sulfate. After removing the solvent, the desired chiral phenyl ring skeleton phosphine-1,2-diphenylethylenediamine ligand was obtained by column chromatography.

[0024] The molar ratio of the 2-diphenylphosphinobenzaldehyde to 1,2-diphenylethylenediamine is 1:1.2.

[0025] The present invention also relates to the application of the above ligand in the asymmetric hydrogenation reaction of C═C, C═N, C═O.

[0026] The chiral phenyl ring skeleton phosphine-1,2-diphenylethylenediamine ligand provided by the present invention can be used in the asymmetric hydrogenation reaction of C═C, C═N, C═O bonds. A catalyst is composed of a tertiary P,N,N ligand of chiral phosphine-alkylamine and Pt, Pd, Ir, Ru or Rh in a molar ratio of 1.1:1 - 2.2:1. The ratio of the reaction substrate to the catalyst is 100 - 10000, and the reaction time is 0.1 - 24 hours.

[0027] The said asymmetric hydrogenation reaction is the catalytic asymmetric hydrogenation reaction of the following types of substrates:

[0028] (1) The catalytic asymmetric hydrogenation reaction of α-aryl ketones;

[0029] (2) The catalytic asymmetric hydrogenation reaction of α,β-unsaturated ketones;

[0030] (3) The catalytic asymmetric hydrogenation of benzene or substituted benzoyl formates;

[0031] Advantages of the present invention:

[0032] The phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton of the present invention is stable in air, has a simple preparation method, high catalytic reaction activity, and the catalyst formed with metal precursors such as Pt, Pd, Ir, Ru or Rh has stable properties, good tolerance to air and humidity. The asymmetric hydrogenation reaction participated by it has mild conditions, is carried out at room temperature, and has a wide applicable range of hydrogen pressure, and the activity and stereoselectivity of the catalyst are not affected from atmospheric pressure to high pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required to be used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other related drawings can be obtained based on these drawings without creative efforts.

[0034] Figure 1 1H NMR spectrum of the phosphine-1,2-diphenylethylenediamine ligand I-1c with a chiral benzene ring skeleton;

[0035] Figure 2 31P NMR spectrum of the phosphine-1,2-diphenylethylenediamine ligand I-1c with a chiral benzene ring skeleton;

[0036] Figure 3 13C NMR spectrum of the phosphine-1,2-diphenylethylenediamine ligand I-1c with a chiral benzene ring skeleton;

[0037] Figure 4 1H NMR spectrum of the phosphine-1,2-diphenylethylenediamine ligand I-1f with a chiral benzene ring skeleton;

[0038] Figure 5 31P NMR spectrum of the phosphine-1,2-diphenylethylenediamine ligand I-1f with a chiral benzene ring skeleton;

[0039] Figure 6 13C NMR spectrum of the phosphine-1,2-diphenylethylenediamine ligand I-1f with a chiral benzene ring skeleton;

[0040] Figure 7 1H NMR spectrum of chiral phenyl(o-tolyl)methanol IV-A;

[0041] Figure 8 1H NMR spectrum of chiral (E)-1,3-diphenylbut-2-en-1-ol IV-B;

[0042] Figure 9 1H NMR spectrum of ethyl (R)-2-hydroxy-2-phenylacetate IV-C. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0043] I. Synthesis of Chiral Ligand

[0044] The chiral ligand designed in the present invention is a phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton obtained by reacting 2-diphenylphosphinobenzaldehyde with 1,2-diphenylethylenediamine.

[0045] The present invention will be described in detail below through examples, but the present invention is not limited to the following examples. Nuclear magnetic resonance was measured by a Bruker nuclear magnetic resonance spectrometer, and high-resolution mass spectrometry (HRMS) was measured by an Agilent 1260 series mass spectrometer.

[0046] Example 1

[0047]

[0048] Under a nitrogen atmosphere, 5 ml of anhydrous methanol (0.2 M) was added to a Schlenk flask containing 2-diphenylphosphinobenzaldehyde (1.0 mmol) and 1,2-diphenylethylenediamine (1.2 mmol). The mixture was reacted at 80 °C for 1 hour. After cooling to room temperature, 2 equiv. of NaBH4 was added. Subsequently, the temperature was raised to 80 °C again and reacted for 3 hours. After cooling to room temperature, water was added to the reaction solution, and then extracted with dichloromethane, dried over anhydrous sodium sulfate. After removing the solvent, the desired phosphine-1,2-diphenylethylenediamine ligand I-1c with a chiral benzene ring skeleton was obtained in a yield of 89% by column chromatography. 1 H NMR(400MHz,CDCl3)δ7.46–6.84(m,24H),4.14(d,J=10.4Hz,1H),3.92(dd,J=2.4Hz,J=13.6Hz,1H),3.85(d,J=10.4Hz,1H),3.68(d,J=13.6Hz,1H),3.49(s,1H),2.71–2.63(m,2H),2.13–2.04(m,2H),1.04(t,J=7.2Hz,3H). 31 P NMR(162MHz,CDCl3):δ-15.6; 1313C NMR (101 MHz, CDCl3) δ 145.7, 145.5, 142.3, 137.5, 137.3, 137.2, 137.0, 136.0, 135.6, 135.4, 134.0, 134.0, 133.8, 133.8, 133.6, 129.9, 129.3, 129.2, 129.2, 129.0, 128.6, 128.6, 128.6, 128.5, 128.5, 127.7, 127.4, 127.1, 126.7, 126.6, 70.1, 62.8, 50.0, 49.7, 43.5, 14.5, 14.4. HRMS cal. for C 37 H 40 N2P + [M + H] + : 543.2954, found: 543.2959. The yield was 86%.

[0049] Example 2

[0050] The reaction temperature in Example 1 was lowered to 60 °C, and the rest was the same as in Example 1, to obtain the desired phosphine-1,2-diphenylethylenediamine ligand I-1c with a chiral benzene ring skeleton in a yield of 86%.

[0051] Example 3

[0052] The 1,2-diphenylethylenediamine compound in Example 1 was changed to the intermediate (III-6) shown in the following figure, and the rest was the same as in Example 1, to obtain the phosphine-1,2-diphenylethylenediamine ligand I-1f with a chiral benzene ring skeleton shown in the following figure, 1 1H NMR (400 MHz, CDCl3) δ 7.41–6.84 (m, 24H), 4.13 (d, J = 10.4 Hz, 1H), 3.94 (dd, J = 2.4 Hz, J = 13.2 Hz, 1H), 3.76 (d, J = 10.4 Hz, 1H), 3.63 (d, J = 13.2 Hz, 1H), 2.70–2.64 (m, 2H), 2.47–2.41 (m, 2H), 1.64–1.48 (m, 8H). 31 31P NMR (162 MHz, CDCl3): δ -15.5. 1313C NMR(101MHz,CDCl3)δ145.5,145.3,141.9,137.5,137.4,137.2,137.1,136.4,135.5,135.4,134.0,133.9,133.8,133.7,133.5,129.6,129.5,129.4,129.2,129.0,128.6,128.5,128.5,128.5,128.4,127.7,127.4,127.2,126.7,76.0,63.4,52.0,50.0,49.8,29.6,26.8.HRMS cal.for C 39 H 42 N2P + [M+H] + :569.3080,found:569.3080.Yield 90%.

[0053]

[0054] II. Asymmetric hydrogenation reaction

[0055] Example 4

[0056] Under nitrogen protection, [Ir(COD)Cl]2(0.001 mmol, 0.5 mol%) and the phosphine-1,2-diphenylethylenediamine ligand (I-1f) with a chiral benzene ring skeleton (0.0011 mmol, 0.55 mol%) were dissolved in ethanol (1.0 ml), stirred at room temperature (25 °C) for 1 hour, and then a solution of the substrate 2-methyldibenzoyl methane (0.2 mmol) in ethanol (1.0 ml) was added. The mixture was placed in a high-pressure reactor, purged with hydrogen three times, and then hydrogen was introduced at 30 bar. The reaction was carried out at room temperature (25 °C) for 12 hours. The hydrogen was slowly released, and after removing the solvent, the product phenyl(o-tolyl)methanol IV-A was separated by silica gel column chromatography. The conversion rate was 99%, and the enantioselectivity was 94% ee. 1 1H NMR(400MHz,CDCl3)δ7.51–7.11(m,9H),5.96(s,1H),2.25(s,1H),2.22(s,3H).

[0057] Example 5

[0058] In Example 4, the substrate was replaced with (E)-1,3-diphenylbut-2-en-1-one, and the rest was the same as in Example 4. The chiral (E)-1,3-diphenylbut-2-en-1-ol IV-B was obtained by the reaction. The conversion rate was 99%, and the enantioselectivity was 98% ee. 11H NMR (400 MHz, CDCl3) δ 7.44–7.21 (m, 10H), 6.00–5.98 (m, 1H), 5.61 (d, J = 8.4 Hz, 1H), 2.17 (d, J = 1.2 Hz, 3H).

[0059] Example 6

[0060] Replace the substrate in Example 4 with ethyl benzoylacetate, and the rest is the same as in Example 4. The reaction gives the product chiral ethyl 2-hydroxy-2-phenylacetate IV-C with a conversion rate of 99% and an enantioselectivity of 98% ee. 1 1H NMR (400 MHz, CDCl3) δ 7.43–7.29 (m, 5H), 5.15 (s, 1H), 4.29–4.12 (m, 2H), 3.47 (s, 1H), 1.22 (t, J = 6.8 Hz, 3H).

Claims

1. A phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton, having the structure of Formula I-1, , characterized in that: Formula I-1 is the following compound 。 2. The phosphine-1,2-diphenylethylenediamine ligand of a chiral benzene ring skeleton according to claim 1, characterized in that: The phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton is synthesized according to the following route: 。 3. The phosphine-1,2-diphenylethylenediamine ligand of a class of chiral benzene ring skeletons according to claim 2, characterized in that: Its preparation method is as follows: Under a nitrogen atmosphere, 5 mL of a 0.2 M methanol solution was added to a Schlenk flask containing 2-diphenylphosphinobenzaldehyde and 1,2-diphenylethylenediamine. The resulting mixture was reacted at 25 - 80 o °C for 1 - 2 hours. After cooling to room temperature, 2 equiv. of NaBH4 was added; subsequently, the reaction was carried out again at 25 - 80 o °C for 3 - 4 hours; after cooling to room temperature, water was added to the reaction solution, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, removal of the solvent, and column chromatography to obtain the desired chiral phenyl ring skeleton phosphine-1,2-diphenylethylenediamine ligand.

4. The preparation method of a phosphine-1,2-diphenylethylenediamine ligand with a chiral benzene ring skeleton according to claim 3, characterized in that: The molar ratio of the 2-diphenylphosphinobenzaldehyde to 1,2-diphenylethylenediamine is 1:1.

2.

5. The phosphine-1,2-diphenylethylenediamine ligand of a chiral benzene ring skeleton according to claim 1, characterized in that: The described ligand is applied to the catalytic asymmetric hydrogenation reactions of the following several types of substrates: (1) The catalytic asymmetric hydrogenation reaction of α-aryl ketones; (2) The catalytic asymmetric hydrogenation reaction of α,β-unsaturated ketones; (3) The catalytic asymmetric hydrogenation of benzene or substituted benzoyl formates.

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