Phosphine catalysts / ligands of a chiral indoloquinoline skeleton and methods of making the same

Abstract

The present application belongs to the technical field of axially chiral phosphine catalysts, and particularly relates to a chiral indoloquinoline skeleton phosphine catalyst / ligand and a preparation method thereof, which is prepared by condensation reaction of a hydroxyl group of a compound 1, axially chiral compound 1-(6-phenylindolo[1,2-a]quinolin-7-yl)naphthalen-2-ol, and a carboxylic acid group in a 2-(arylphosphino or alkylphosphino)benzoic acid compound 2 under the condition of a molecular sieve as a condensing agent, wherein the catalyst of the present application exhibits excellent catalytic performance in specific asymmetric catalytic reactions, can effectively overcome the deficiencies of traditional axially chiral phosphine catalysts in terms of chiral regulation ability and substrate applicability, and provides a brand-new design strategy for developing an efficient and highly selective asymmetric catalytic system.

Description

Technical Field

[0001] This invention belongs to the field of axial chiral phosphine catalyst technology, and particularly relates to a chiral indoquinoline skeleton phosphine catalyst / ligand and its preparation method. Background Technology

[0002] Asymmetric catalysis is a key technology for constructing chiral compounds, and the structural design of catalysts plays a decisive role in improving reaction activity and stereoselectivity. Axially chiral phosphine catalysts, due to their unique chiral control capabilities, have been widely used in various asymmetric catalytic reactions, such as hydrogenation, coupling, and cyclization, effectively improving the optical purity of the products. Currently, biphenyl and binaphthalene (e.g., BINAP / Segphos) axially chiral phosphine catalysts have become important representatives in this field, achieving significant results in various reaction systems. However, the framework types of these catalysts are relatively fixed, and their chiral control capabilities and applicability still have certain limitations. Furthermore, current innovative research on axially chiral catalysts remains relatively limited, especially in expanding catalyst framework types, optimizing the catalytic chiral environment, and enhancing catalytic activity, which still face many challenges. Therefore, designing and developing axially chiral phosphine catalysts with novel framework structures that provide more precise chiral control capabilities is of great significance for promoting the development of asymmetric catalysis technology. Summary of the Invention

[0003] The purpose of this invention is to provide a chiral indo-quinoline skeletal phosphine catalyst / ligand and its preparation method. Its core structure is based on the indo-quinoline skeletal framework. By introducing the indo-quinoline skeletal framework with unique multi-coordination ability, the catalyst of this invention retains the advantages of traditional axial chiral phosphine catalysts while further optimizing the chiral environment, thereby significantly improving catalytic efficiency and stereoselectivity.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0005] A method for preparing a chiral indophylloquinoline skeleton phosphine catalyst / ligand is disclosed, which uses compound 1, an axially chiral compound 1-(6-phenylindophyllo[1,2-a]quinophylline-7-yl)naphth-2-ol, as a key precursor. The hydroxyl group of compound 1 reacts with the carboxylic acid group of compound 2-(arylphosphino or alkylphosphino)benzoic acid under the condition of molecular sieve as a condensing agent to form the catalyst. This invention is the first to use molecular sieve as a condensing agent, which not only achieves efficient condensation but also meets the requirements of green and environmentally friendly process. The synthetic route is shown below:

[0006] .

[0007] Furthermore, the organic solvent used in the reaction was dichloromethane. After the reaction was completed, the product was extracted with ethyl acetate and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and then recrystallized to obtain compound 3.

[0008] Another object of the present invention is to provide a phosphine catalyst / ligand with a chiral indoquinoline skeleton prepared by the above method.

[0009] An application of a ligand in an asymmetric 1,4-conjugated addition reaction, whereby the amount of palladium catalyst can be reduced to 0.2% without affecting reaction efficiency and yield.

[0010] The advantages of this invention are as follows: This invention is the first to use a 4Å molecular sieve as a catalyst to achieve efficient construction of esterification products. The molecular sieve selectively adsorbs the generated water, reducing the water concentration in the system, disrupting the reaction equilibrium, and shifting the esterification reaction towards ester formation. It does not participate in the reaction itself, but only acts as a physical dehydrating agent. Compared to traditional condensing agents such as concentrated sulfuric acid, phosphoric acid, or thionyl chloride, molecular sieve operation is milder, non-corrosive, and produces no byproducts, making it more environmentally friendly. The catalyst prepared by this invention exhibits excellent catalytic performance in specific asymmetric catalytic reactions, effectively overcoming the shortcomings of traditional axial chiral phosphine catalysts in terms of chiral control capability and substrate applicability. This provides a novel design strategy for developing efficient and highly selective asymmetric catalytic systems. Attached Figure Description

[0011] Figure 1 This is the 1H NMR spectrum of the chiral indoquinoline skeleton phosphine catalyst / ligand 3a prepared in Example 1 of this invention. Detailed Implementation

[0012] The synthesis process of compound 1 in this application is based on the description in ACS Catal., 2025, 15, 201–210. The chiral indoquinoline skeleton phosphine catalyst / ligand prepared in this invention is compound 3, which is presented in the examples as four specific substances, namely compounds 3a-3d described in Examples 1-4.

[0013] Example 1

[0014] Synthesis of compound 3a: 2-Diphenylphosphine benzoic acid (2a) (0.22 mmol, 1.1 equivalent) was added to dichloromethane (DCM, 2 mL), followed by compound 1 (0.2 mmol, 1.0 equivalent) and 4 Å molecular sieve (200 mg). After the reaction was complete, the product was extracted with ethyl acetate (EtOAc) and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate (Na₂SO₄) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1) and then recrystallized to give compound 3a (yield 82%, enantiomeric excess 99%). 1 H NMR (500 MHz, CDCl3) δ 8.69(d, J = 8.3 Hz, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.63 (m,6H), 7.34 (m, 4H), 7.26 (m, 3H), 7.18 (m, 9H), 7.03 (d, J = 6.4 Hz, 3H), 6.97(t, J = 7.5 Hz, 1H), 6.89 – 6.74 (m, 2H), 6.62 (t, J = 7.2 Hz, 2H). 13 C NMR (126MHz, CDCl3) δ 164.6, 157.8, 146.8, 141.3, 141.1, 137.7, 137.6, 137.1, 136.1,134.1, 134.0, 133.9, 133.8, 133.8,133.6, 133.3, 133.2, 132.5, 132.0, 131.4,130.5, 130.3, 130.3, 129.9, 129.0, 128.6, 128.4, 128.4, 128.3, 128.3, 127.9,127.9, 127.7, 126.5, 126.4, 126.1, 126.1, 125.2, 124.9, 124.3, 123.0, 122.7, 122.6, 121.5, 114.8, 114.4, 108.6.

[0015] The specific synthesis process is as follows:

[0016] .

[0017] Example 2

[0018] Synthesis of compound 3b: 2-Dicyclohexylphosphonic acid 2b (0.22 mmol, 1.1 equivalent) was added to dichloromethane (DCM, 2 mL), followed by compound 1 (0.2 mmol, 1.0 equivalent) and 4 Å molecular sieve (200 mg). After the reaction was complete, the product was extracted with ethyl acetate (EtOAc) and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80 / 1) and then recrystallized to give compound 3b (67% yield, 99% enantiomeric excess). 1 H NMR (500 MHz, CDCl3) δ 8.29 (dd, J = 7.3, 1.3 Hz, 1H), 8.10 – 8.04 (m, 1H), 8.01 (dd, J = 5.9, 1.3 Hz, 1H), 7.93(m, 2H), 7.87 (dd, J = 6.3, 1.4 Hz, 1H), 7.81 – 7.73 (m, 3H), 7.68 (dd, J = 7.2,1.2 Hz, 1H), 7.65 – 7.59 (m, 2H), 7.57 – 7.44 (m, 7H), 7.44 – 7.36 (m, 2H),7.35 – 7.24 (m, 2H), 2.51 (p, J = 7.3 Hz, 2H), 1.81 – 1.66 (m, 4H), 1.60 – 1.44 (m, 8H), 1.44 – 1.32 (m, 8H).

[0019] 13C NMR (126 MHz, CDCl3) δ 166.2, 151.3, 147.0, 146.6,140.8, 136.2,135.9, 132.4, 132.1, 131.6, 131.3, 130.8, 130.4, 130.3, 129.4, 129.0, 128.5,128.1, 128.0, 128.0, 127.9, 127.5, 127.5, 127.4, 127.2, 127.1,127.0, 126.4,125.2, 124.8, 124.2, 123.5, 120.2, 118.5, 117.2, 111.6, 34.8, 31.4, 27.2, 26.6.

[0020] The specific synthesis process is as follows:

[0021] .

[0022] Example 3

[0023] Synthesis of compound 3c: 2-Di-tert-butylphosphine benzoic acid 2c (0.22 mmol, 1.1 equivalent) was added to dichloromethane (DCM, 3 mL), followed by compound 1 (0.2 mmol, 1.0 equivalent) and 4 Å molecular sieve (200 mg). After the reaction was complete, the product was extracted with ethyl acetate (EtOAc) and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80 / 1) and then recrystallized to give compound 3c (80% yield, 99% enantiomeric excess).

[0024] 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.4, 1H), 8.10 – 8.04 (m, 1H), 8.01 (dd, J= 6.0, 1.5 Hz, 1H), 7.97 – 7.89 (m, 2H), 7.87 (d, J = 6.2, 1H), 7.80– 7.73 (m, 3H), 7.68 (dd, J= 7.1, 1.2 Hz, 1H), 7.62 (m, 1H), 7.56 – 7.45 (m,7H), 7.45 – 7.40 (m, 2H), 7.36 (dd, J = 6.2, 1.5 Hz, 1H), 7.35 – 7.24 (m,2H), 1.13 (s, 18H). 13 C NMR (126 MHz, CDCl3) δ 166.0, 151.3, 146.6,140.8,138.1, 138.0, 136.2, 135.9, 134.1, 132.1, 130.8, 130.4, 129.4, 129.0, 128.5,128.3, 128.1, 128.0, 128.0, 127.9, 127.5, 127.5, 127.4, 127.2, 127.1,127.0,126.4, 125.2, 124.8, 124.2, 123.5, 120.2, 118.5, 117.2, 111.6, 29.8, 29.3.

[0025] The specific synthesis process is as follows:

[0026] .

[0027] Example 4

[0028] Synthesis of compound 3d: 2-Diadamylphosphonic acid 2d (0.22 mmol, 1.1 equivalent) was added to dichloromethane (DCM, 3 mL), followed by compound 1 (0.2 mmol, 1.0 equivalent) and 4 Å molecular sieve (200 mg). After the reaction was complete, the product was extracted with ethyl acetate (EtOAc) and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 1) and then recrystallized to give compound 3d (65% yield, 99% enantiomeric excess).

[0029] 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.3, 1H),8.12 – 8.05 (m, 1H),8.01 (dd, J = 5.9, 1.3 Hz, 1H), 7.97 – 7.91 (m, 2H), 7.87 (d, J= 6.2, 1H), 7.81– 7.73 (m, 3H), 7.68 (dd, J = 7.2, 1.2 Hz, 1H), 7.62 (ddd, J = 6.8, 5.8, 1.2 Hz,1H), 7.57 – 7.45 (m, 7H), 7.44 – 7.39 (m, 2H), 7.37 (dd, J = 6.2, 1.5 Hz, 1H), 7.36 – 7.24 (m, 2H), 2.00 – 1.88 (m, 6H), 1.75 – 1.58 (m, 24H). 13 C NMR (126MHz, CDCl3) δ 166.0, 151.3, 147.6, 146.6, 140.8, 136.2, 135.9, 134.1, 134.1,132.1, 131.0, 130.8, 130.4, 129.4,129.0, 128.9, 128.5, 128.1, 128.0, 128.0,127.9, 127.5, 127.5, 127.4, 127.2, 127.1, 127.0, 126.4, 125.2, 124.8, 124.2,123.5, 120.2, 118.5, 117.2, 111.6, 49.2, 43.7, 43.0, 38.7, 37.1, 29.8.

[0030] The specific synthesis process is as follows:

[0031] .

[0032] Application examples

[0033] When ligand 3a prepared in Example 1 is applied to an asymmetric 1,4-conjugated addition reaction, the required amount of palladium catalyst can be reduced to 0.2% compared with existing ligands. This significantly improves catalytic efficiency and effectively reduces costs without affecting reaction efficiency and yield, fully demonstrating the significant advantages of the ligand involved in this patent. The specific reaction process is as follows:

[0034]

[0035] Under argon protection, [Rh(C2H4)2Cl]2 (0.003 mmol), ligand (0.007 mmol), KOH (0.1 mmol), and [1,1'-biphenyl]-4-ylboronic acid 5 (0.2 mmol) were added to a Schlenk tube, followed by the addition of solvent (tetrahydrofuran / water = 1 / 0.1 mL). Subsequently, 2-cyclohexen-1-one 4 (0.1 mmol) was injected into the reaction solution. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL) and quenched with water (5 mL); the organic layer was separated, and the aqueous phase was extracted twice with ethyl acetate. All organic phases were combined, washed with saturated brine, and dried over Na2SO4. After solvent removal, the product was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 15 / 1) to finally obtain product 6 (97% yield, 98% ee).

Claims

1. A method for preparing a phosphine ligand with a chiral indo-quinoline skeleton, characterized in that: It is prepared by using axially chiral compound 1-(6-phenylindolo[1,2-a]quinoline-7-yl)naphthyl-2-ol as a key precursor. The hydroxyl group of compound 1 reacts with the carboxylic acid group of compound 2-(arylphosphino or alkylphosphino)benzoic acid under the condition of molecular sieve as a condensing agent. The synthetic route is shown below: 。 2. The method for preparing the phosphine ligand of the chiral indo-quinoline skeleton as described in claim 1, characterized in that: The organic solvent used in the reaction was dichloromethane. After the reaction was completed, the product was extracted with ethyl acetate and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and then recrystallized to obtain compound 3.

3. Phosphine ligands with a chiral indoline quinoline skeleton prepared by the method of claim 1 or 2.

4. The application of the ligand as described in claim 3, characterized in that: This ligand is used in asymmetric 1,4-conjugated addition reactions, with the palladium catalyst used in molar amounts as low as 0.2% of the substrate.

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