Chiral p, n, n ligands, their preparation and use

Abstract

The application provides a kind of chiral P, N, N ligand and its preparation method and application in asymmetric hydrogenation reaction. 2-diphenylphosphinyl phenethylamine is mixed with 6-phenylpyridine-2-formaldehyde, nitrogen is filled, methanol is added, the formed mixture is refluxed, after cooling, NaBH4 is added. Then, the mixture is refluxed again. Cooling, water is added, dichloromethane is extracted, anhydrous sodium sulfate is dried, after removing solvent, the desired chiral P, N, N ligand is obtained by column chromatography. The catalyst formed by the chiral ligand described in the application and Mn, Ir-, Ru- and other metal precursors has excellent catalytic activity and stereoselectivity in the catalytic asymmetric hydrogenation reaction of C=C, C=N and C=O double bond. The enantioselectivity is as high as 99% ee, and the TON is as high as 100000.

Description

Technical Field

[0001] This invention relates to a method for preparing a novel class of chiral P,N,N ligands. This invention also relates to the application of these ligands in asymmetric hydrogenation reactions of C=C, C=N, and C=O double bonds. Background Technology

[0002] In recent years, stable octahedral Mn(I) complexes have been shown to be potential alternatives to noble metals in asymmetric hydrogenation of C=O bonds. Mn(CO)5Br is currently the only practical Mn(I) precursor for asymmetric hydrogenation, therefore, the design and synthesis of new chiral tridentate ligands is key to improving the performance of manganese-catalyzed asymmetric hydrogenation reactions. In 2017, Kirchner reported a class of P,N,P tridentate aldehyde imine ligands containing a ferrocene framework. The complexes of these ligands with Mn(CO)5Br can be applied to the asymmetric hydrogenation of some ketones and have good enantioselectivity [[a]A. Zirakzadeh, SRMMde Aguiar, B. Sto¨ger, M. Widhalm and K. Kirchner, ChemCatChem, 2017, 9, 1744–1748.]. In the same year, Clarke reported a class of ligands containing a ferrocene framework, P,N(H),N tridentate. The complex of this ligand, lacking an imine structure, with Mn(CO)5Br also showed good reactivity and enantioselectivity in the asymmetric hydrogenation of ketones [(b)MB Widegren, GJ Harkness, AMZ Slawin, DB Cordes and MLClarke, Angew. Chem., Int. Ed., 2017, 56, 5825–5828. (c)MB Widegren and MLClarke, Catal. Sci. Technol., 2019, 9, 6047–6058.]. In the ligands used in the asymmetric hydrogenation of ketones catalyzed by manganese, a planar chiral ferrocene framework is not essential. Beller reported a class of non-ferrocene-based P,N,P tridentate ligands complexed with Mn(CO)5Br, which, although failing to yield good results in the asymmetric hydrogenation of aromatic ketones, demonstrated excellent selectivity and reactivity in the asymmetric hydrogenation of aliphatic ketones, as well as this [(d)M.Garbe, K.Junge,S.Walker,Z.Wei,H.Jiao,A.Spannenberg,S.Bachmann,M.Scalone andM.Beller,Angew.Chem.,Int.Ed.,2017,56,11237–11241.(e)M.Garbe,Z.Wei,B.Tannert,A.Spannenberg,H.Jiao,S.Bachmann,M.Scalone,K.Junge andM.Beller,Adv.Synth.Catal.,2019,361,1913–1920.].However, while the asymmetric hydrogenation of a variety of simple ketones has been successfully achieved in these pioneering experiments, the substrate range of products with high ee values ​​obtained is relatively narrow.

[0003] Although significant progress has been made in manganese-catalyzed asymmetric hydrogenation of ketones, the asymmetric hydrogenation of other types of ketones, such as acylpyridines, α,β-unsaturated ketones, and α-halogen-substituted ketones, has not yet been reported. Furthermore, there is considerable room for improvement in the asymmetric hydrogenation of C=N double bonds, while significant challenges remain in the asymmetric hydrogenation of C=C double bonds. Therefore, designing and synthesizing novel chiral bidentate, tripentate, or tetradentate ligands, or searching for other manganese catalytic precursors to improve the catalytic activity of Mn(I) complexes, remains of great research significance. Summary of the Invention

[0004] This invention discloses a class of chiral P,N,N ligands and their preparation methods.

[0005] To achieve the above objectives, the present invention provides a chiral P,N,N ligand with the following structure:

[0006]

[0007] In the formula:

[0008] Ar represents phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, or 2,4,6-trisubstituted aryl groups with a C6-C carbon number 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 represents hydrogen, 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] The chiral P, N, N ligands described herein have a dominant absolute configuration of S or R.

[0011] The chiral P,N,N ligands described above have an aromatic ring with 6-3 carbon atoms in the R group. 60 (preferably C6-C) 30 More preferably C6-C 24 The aromatic group of ) is preferably phenanthrene I-4b.

[0012]

[0013] This invention provides a method for preparing chiral P,N,N ligands: chiral P,N,N ligands are synthesized according to the following route:

[0014]

[0015] In the formula:

[0016] Ar represents phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, or 2,4,6-trisubstituted aryl groups with a C6-C carbon number 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.

[0017] R represents hydrogen, 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 ).

[0018] Under a nitrogen atmosphere, methanol solution (2-diphenylphosphine-phenylethylamine final concentration 0.2-1.0 M) was added to a container containing 2-diphenylphosphine-phenylethylamine and 6-phenylpyridine-2-carboxaldehyde. The resulting mixture was refluxed at 70-80 °C for 1-2 hours. After cooling to room temperature, 2-3 equiv. (relative to the amount of 2-diphenylphosphine-phenylethylamine) NaBH4 was added. Subsequently, the mixture was refluxed again at 70-80 °C for 3-4 hours. After cooling to room temperature, water was added to the reaction solution (water to mixture volume ratio 3:1-5:1), and the mixture was extracted with dichloromethane (volume 10-50 mL x 3). After drying with anhydrous sodium sulfate and removing the solvent, the desired chiral P, N, N ligands were obtained.

[0019] The molar ratio of 2-diphenylphosphinophenethylamine to 6-phenylpyridine-2-carboxaldehyde is 1:1.2-1:2.0.

[0020] The catalysts formed by the chiral P,N,N ligands and metal precursors such as Mn, Ir-, and Ru- of this invention exhibit excellent catalytic activity and stereoselectivity for the asymmetric hydrogenation of C=C, C=N, and C=O double bonds, with an enantioselectivity as high as 99% ee and a TON as high as 100,000.

[0021] The present invention also relates to the application of the above-mentioned ligands in one or more asymmetric hydrogenation reactions containing C=C, C=N, or C=O reaction substrates.

[0022] The chiral P,N,N ligands provided by this invention can be used in one or more asymmetric hydrogenation reactions of C=C, C=N, and C=O bonds. The chiral P,N,N ligands are combined with one or more of Mn, Ir, Ru, or Rh in a molar ratio of 1.1:1 to 2.2:1 with the metal to form a catalyst. The ratio of reaction substrate to catalyst is 100-10000 (preferably 100-1000, more preferably 100-500), and the reaction time is 0.1-24 hours.

[0023] The asymmetric hydrogenation reaction described herein is a catalytic asymmetric hydrogenation reaction of the following types of substrates:

[0024] (1) Catalytic asymmetric hydrogenation of α-aryl ketones;

[0025] (2) Catalytic asymmetric hydrogenation of α,β-unsaturated ketones;

[0026] (3) Catalytic asymmetric hydrogenation of benzene or substituted benzoyl carbamates;

[0027] The beneficial effects of this invention are:

[0028] The chiral P,N,N ligands of the present invention are stable in air, have a simple preparation method, and exhibit high catalytic activity. The catalysts formed with metal precursors such as Mn, Ir, Ru, or Rh are stable and have good tolerance to air and humidity. The asymmetric hydrogenation reaction in which they participate is mild and can be carried out at room temperature. The applicable hydrogen pressure range is wide, and the activity and stereoselectivity of the catalyst are not affected from atmospheric pressure to high pressure. Attached Figure Description

[0029] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings 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 should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0030] Figure 1 The 1H NMR spectrum of I-2a, a compound with P, N, N ligands of chiral pyridine-phenylethylamine;

[0031] Figure 2 The phosphorus NMR spectrum of I-2a, a compound with P, N, N ligands of chiral pyridine-phenylethylamine;

[0032] Figure 3 The 1H NMR spectrum of I-4a, a compound with P,N,N ligands of chiral pyridine-phenylethylamine;

[0033] Figure 4 The phosphorus NMR spectrum of the chiral pyridine-phenylethylamine compound I-4a with P,N,N ligands;

[0034] Figure 5 The 1H NMR spectrum of I-4b, a compound with P,N,N ligands of chiral pyridine-phenethylamine;

[0035] Figure 6 The phosphorus NMR spectrum of the chiral pyridine-phenethylamine P,N,N ligand compound I-4b;

[0036] Figure 7 The 1H NMR spectrum of N-(2-(hydroxy(phenyl)methyl)phenyl)acetamide IV-A;

[0037] Figure 8 The 1H NMR spectrum of chiral (E)-1,3-diphenylbut-2-en-1-ol IV-B;

[0038] Figure 9 The 1H NMR spectrum of chiral ethyl 2-hydroxy-2-phenylacetate IV-C. Detailed Implementation

[0039] The chiral ligands designed in this invention are obtained by reacting 2-diphenylphosphinophenethylamine with 6-phenylpyridine-2-carboxaldehyde to obtain chiral P,N,N ligands.

[0040] The present invention is described in detail below through embodiments, but the present invention is not limited to the following embodiments. Nuclear magnetic resonance (NMR) measurements were performed using a Bruker NMR spectrometer, and high-resolution mass spectrometry (HRMS) measurements were performed using an Agilent 1260 series mass spectrometer.

[0041] I. Synthesis of chiral ligands

[0042] Example 1

[0043]

[0044] Under a nitrogen atmosphere, 5 mL of anhydrous methanol (0.2 M) was added to a Shoelock flask containing 1.0 mmol of 2-diphenylphosphine-phenylethylamine and 1.2 mmol of 6-phenyl-2-pyridylcarboxaldehyde. The mixture was refluxed at 80 °C for 1 hour. After cooling to room temperature, 2 equiv (relative to 2-diphenylphosphine-phenylethylamine)NaBH4 was added. Subsequently, the mixture was refluxed again at 80 °C for 3 hours. After cooling to room temperature, 15 mL of water was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The mixture was dried over anhydrous sodium sulfate, and after solvent removal, column chromatography was used to obtain the desired chiral P,N,N ligand I-2a.

[0045] 1 H NMR (400MHz, CDCl3) δ8.00–6.87 (m, 22H), 4.82–4.75 (m, 1H), 3.67 (dd, J = 14.0Hz, J = 8.0Hz, 2H), 2.26 (s, 1H), 1.29 (d, J = 6.4Hz, 2H). 31 P NMR (162MHz, CDCl3): δ-17.4; HRMS cal.for C 42 H 36 N2P + [M+H] + : 473.2141, found: 473.2146. Yield is 93%.

[0046] Example 2

[0047] In Example 1, 2-diphenylphosphinophenethylamine was replaced with the intermediate (III-4a) shown below, and the remaining processes and conditions were the same as in Example 1, to obtain the chiral P,N,N ligand I-4a shown below. 1H NMR (400MHz, CDCl3) δ7.98–6.86(m,21H),4.60–4.57(m,1H),4.04 (s,2H),2.95–2.75(m,2H),2.24–2.07(m,2H),1.86(s,1H),1.74–1.58 (m,2H). 31 P NMR (162MHz, CDCl3): δ-16.4.HRMS cal.for C 39 H 42 N2P + [M+H] + :499.2298, found:499.2300. Yield 88%.

[0048]

[0049] Example 3

[0050] In Example 2, 6-phenyl-2-pyridylcarboxaldehyde was replaced with the intermediate shown below (III-1b), and the remaining processes and conditions were the same as in Example 2, yielding the chiral P,N,N ligand I-4b shown below. 1 H NMR (400MHz, CDCl3) δ8.71–6.94 (m, 25H), 4.63 (t, J = 2.8Hz, 1H), 4.12(s,2H),2.91–2.71(m,2H),2.24–2.08(m,2H),1.84(t,J=4.8Hz,1H),1.71–1.57(m,2H). 31 P NMR (162MHz, CDCl3): δ-16.4; HRMS cal. for C 42 H 36 N2P + [M+H] + :599.2611,found:599.2610. Yield is 92%.

[0051]

[0052] II. Asymmetric hydrogenation reaction

[0053] Example 4

[0054] Under nitrogen protection, Mn(CO)5Br (0.002 mmol, 1 mol%) and chiral P,N,N ligand (I-4b) (0.0022 mmol, 1.1 mol%) were dissolved in ethanol (1.0 mL). The mixture was stirred at room temperature (25 °C) for 1 hour. A solution of the substrate 2-acetamidobenzophenone (0.2 mmol) in ethanol (1.0 mL) was added. The mixture was placed in an autoclave, purged three times with hydrogen, and then purged with 30 bar of hydrogen. The reaction was carried out at room temperature (25 °C) for 12 hours. Hydrogen was slowly released, and after solvent removal, the product N-(2-(hydroxy(phenyl)methyl)phenyl)acetamide IV-A was obtained by silica gel column chromatography. The conversion was 99%, and the enantioselectivity was 98% ee. 1 H NMR (400MHz, CDCl3) δ8.53 (d, J = 3.6 Hz, 1H), 7.94- 7.07 (m, 9H), 5.85 (s, 1H), 3.82 (d, J = 22.0 Hz, 1H), 1.8 (d, J = 2.4 Hz, 1H).

[0055] Example 4

[0056] In Example 3, the substrate was replaced with (E)-1,3-diphenylbut-2-en-1-one, and the remaining procedures and conditions were the same as in Example 3. The reaction yielded chiral (E)-1,3-diphenylbut-2-en-1-ol IV-B with a conversion of 99% and an enantioselectivity of 98% ee. 1 HNMR (400MHz, CDCl3) δ7.44–7.21 (m, 10H), 6.00–5.98 (m, 1H), 5.61 (d, J = 8.4Hz, 1H), 2.17 (d, J = 1.2Hz, 3H).

[0057] Example 5

[0058] In Example 3, the substrate was replaced with ethyl benzoyl ester, and the remaining procedures and conditions were the same as in Example 3. The reaction yielded chiral ethyl 2-hydroxy-2-phenylacetate IV-C with a conversion of 99% and an enantioselectivity of 98% ee. 1 H NMR (400MHz, CDCl3) δ7.43–7.29(m,5H), 5.15(s,1H),4.29–4.12(m,2H),3.47(s,1H),1.22(t,J=6.8Hz,3H).

Claims

1. A chiral P,N,N ligand, characterized in that: The structural formula is as follows: 。 2. A method for synthesizing the chiral P,N,N ligand as described in claim 1, wherein the chiral P,N,N compound is synthesized via the following route: 。 3. The method for synthesizing chiral P, N, N ligands according to claim 2 is as follows: Under a nitrogen atmosphere, the intermediate ( S A methanol solution was added to a container containing 1-8-diphenylphosphino-1,2,3,4-tetrahydronaphthalene-1-amine and the intermediate 6-(9-phenanthyl)-2-pyridinecarboxaldehyde. The resulting mixture was refluxed at 80°C for 1 hour. After cooling to room temperature, a solution relative to the intermediate ( S The amount of 2 equiv. of 8-diphenylphosphino-1,2,3,4-tetrahydronaphthalene-1-amine in NaBH4 was then refluxed again at 80 °C for 3 hours. After cooling to room temperature, water was added to the reaction solution, followed by extraction with dichloromethane, drying with anhydrous sodium sulfate, and after solvent removal, the desired chiral P,N,N ligands were obtained by separation.

4. The application of the chiral P, N, N ligand of claim 1 in asymmetric hydrogenation reactions, wherein the asymmetric hydrogenation reaction is a catalytic asymmetric hydrogenation reaction of the following types of substrates: (1) Catalytic asymmetric hydrogenation of α-aryl ketones; (2) Catalytic asymmetric hydrogenation of α,β-unsaturated ketones; (3) Catalytic asymmetric hydrogenation of benzoyl carbamate.

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