Phosphine catalyst / ligand of chiral indoloquinoline skeleton and preparation method of phosphine catalyst / ligand

Abstract

The invention belongs to the technical field of axially chiral phosphine catalysts, and particularly relates to a phosphine catalyst / ligand of a chiral indoloquinoline skeleton and a preparation method of the phosphine catalyst / ligand, and the phosphine catalyst / ligand is prepared by taking a compound 1 axially chiral compound 1-(6-phenylindolo [1, 2-a] quinazoline-7-yl) naphthalene-2-alcohol as a key precursor and adding a compound 2-(2-phenylindolo [1, 2-a] quinazoline-7-yl) naphthalene-2-alcohol as a ligand. A hydroxyl group of the compound 1 and a carboxylic acid group in a 2-(aryl phosphino or alkyl phosphino) benzoic acid compound 2 are subjected to a condensation reaction under the condition that a molecular sieve serves as a condensing agent, and the catalyst is prepared. The defects of a traditional axially chiral phosphine catalyst in the aspects of chiral regulation and control capability and substrate applicability can be effectively overcome, and a brand new design strategy is provided for developing an efficient and high-selectivity asymmetric catalytic system.

Description

Technical Field

[0001] The invention belongs to the technical field of axial chiral phosphine catalysts, and in particular relates to a phosphine catalyst / ligand of a chiral indole-quinoline skeleton and a preparation method thereof. Background Art

[0002] Asymmetric catalysis is a key technology for constructing chiral compounds, where catalyst structural design plays a crucial role in enhancing reaction activity and stereoselectivity. Axially chiral phosphine catalysts, due to their unique chiral control capabilities, have been widely used in a variety of asymmetric catalytic reactions, such as hydrogenations, couplings, and cyclizations, effectively improving the optical purity of products. Currently, biphenyl and binaphthyl (e.g., BINAP / Segphos)-based axially chiral phosphine catalysts have become prominent representatives in this field, achieving remarkable results in a variety of reaction systems. However, these catalysts have a relatively fixed framework type, which limits their chiral control capabilities and applicability. Furthermore, innovative research on axially chiral catalysts remains limited, particularly in expanding catalyst framework types, optimizing the catalytic chiral environment, and enhancing catalytic activity. Therefore, the design and development of axially chiral phosphine catalysts with novel framework structures that offer more precise chiral control capabilities is crucial for advancing asymmetric catalysis. Summary of the Invention

[0003] The purpose of the present invention is to provide a phosphine catalyst / ligand with a chiral indoloquinoline skeleton and a preparation method thereof. Its core structure is based on the indoloquinoline skeleton. By introducing the indoloquinoline skeleton with unique multi-coordination ability, the catalyst of the present invention further optimizes the chiral environment while retaining the advantages of traditional axial chiral phosphine catalysts, thereby significantly improving the catalytic efficiency and stereoselectivity.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is: A method for preparing a chiral indoloquinoline skeleton phosphine catalyst / ligand is provided. The method uses a compound 1, an axial chiral compound 1-(6-phenylindolo[1,2-a]quinolin-7-yl)naphthalen-2-ol, as a key precursor. The hydroxyl group of the compound 1 and the carboxylic acid group of the 2-(arylphosphino or alkylphosphino)benzoic acid compound 2 undergo an efficient condensation reaction under the condition that a molecular sieve is used as a condensation agent. The present invention uses a molecular sieve as a condensation agent for the first time, which not only achieves efficient condensation but also meets the requirements of a green and environmentally friendly process. The synthesis route is as follows: .

[0005] Furthermore, the organic solvent used in the reaction is dichloromethane. After the reaction is completed, the product is extracted with ethyl acetate and washed with brine. The obtained organic phase is dried over anhydrous sodium sulfate and then filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography and then recrystallized to obtain compound 3.

[0006] Another object of the present invention is to provide a chiral indole-quinoline skeleton phosphine catalyst / ligand prepared by the above method.

[0007] A ligand is used in an asymmetric 1,4-conjugate addition reaction. The amount of palladium catalyst used can be reduced to 0.2% without affecting the reaction efficiency and yield.

[0008] The advantages of the present invention are: the present invention uses 4Å molecular sieve as a catalyst for the first time to achieve efficient construction of esterification products; the molecular sieve selectively adsorbs generated water, reduces the water concentration in the system, breaks the reaction equilibrium, and shifts the esterification reaction toward ester formation; the molecular sieve itself does not participate in the reaction but only acts as a physical dehydrating agent; compared with traditional condensation agents such as concentrated sulfuric acid, phosphoric acid or thionyl chloride, the molecular sieve is gentler to operate, non-corrosive, free of by-products, and more environmentally friendly; the catalyst prepared by the method of the present invention exhibits excellent catalytic performance in specific asymmetric catalytic reactions, can effectively overcome the shortcomings of traditional axial chiral phosphine catalysts in terms of chirality control ability and substrate applicability, and provides a new design strategy for the development of efficient and highly selective asymmetric catalytic systems. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 This is the H NMR spectrum of the chiral indoloquinoline skeleton phosphine catalyst / ligand 3a prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0010] The synthesis process of compound 1 in this application is based on the records of ACS Catal., 2025, 15, 201–210. The chiral indole-quinoline skeleton phosphine catalyst / ligand prepared in the present invention, namely compound 3, is presented in the examples as four specific substances, namely compounds 3a-3d described in Examples 1-4.

[0011] Example 1 Synthesis of compound 3a: 2-Diphenylphosphinobenzoic acid (2a) (0.22 mmol, 1.1 equiv) was added to dichloromethane (DCM, 2 mL), followed by compound 1 (0.2 mmol, 1.0 equiv) and 4Å molecular sieves (200 mg). After completion of the reaction, 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, and 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 provide 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. The specific synthesis process is as follows: .

[0012] Example 2 Synthesis of compound 3b: 2-Dicyclohexylphosphinobenzoic acid 2b (0.22 mmol, 1.1 equiv) was added to dichloromethane (DCM, 2 mL), followed by compound 1 (0.2 mmol, 1.0 equiv) and 4Å molecular sieves (200 mg). After completion of the reaction, 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, and 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 provide compound 3b (yield 67%, enantiomeric excess 99%). 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). 13 C 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. The specific synthesis procedure is as follows: .

[0013] Example 3 Synthesis of compound 3c: To 2-di-tert-butylphosphinobenzoic acid 2c (0.22 mmol, 1.1 equiv) in dichloromethane (DCM, 3 mL) was added compound 1 (0.2 mmol, 1.0 equiv) followed by 4A molecular sieves (200 mg) sequentially. After completion of the reaction, the product was extracted with ethyl acetate (EtOAc) and washed with brine. The resulting organic phase was dried over anhydrous sodium sulfate (Na2S04) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / Ethyl acetate = 80 / 1) followed by recrystallization to give compound 3c (yield 80%, enantiomeric excess 99%).

[0014] 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. The specific synthesis procedure is as follows: .

[0015] Example 4 Synthesis of compound 3d: 2-Diadamantylphosphinobenzoic acid 2d (0.22 mmol, 1.1 equiv) was added in dichloromethane (DCM, 3 mL), followed by compound 1 (0.2 mmol, 1.0 equiv), and 4A molecular sieves (200 mg) sequentially. After the reaction was completed, 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, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / Ethyl acetate = 100 / 1) followed by recrystallization to obtain compound 3d (yield 65%, enantiomeric excess 99%).

[0016] 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). 13C 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. The specific synthesis process is as follows: .

[0017] Application Examples When the ligand 3a prepared in Example 1 is applied to an asymmetric 1,4-conjugate addition reaction, the amount of palladium catalyst required can be reduced to 0.2% compared to existing ligands. This significantly improves the catalytic efficiency and effectively reduces the cost without affecting the reaction efficiency and yield, fully demonstrating the significant advantages of the ligand involved in this patent. The specific reaction process is as follows: Under argon, [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 added to the reaction solution. The mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and quenched with water (5 mL). After separation of the organic layer, the aqueous phase was extracted twice with ethyl acetate. All organic phases were combined, washed with saturated brine, and dried over Na2SO4. After removal of the solvent, the product was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 15 / 1) to obtain product 6 in 97% yield, 98% ee.

Claims

1. A method for preparing a chiral indoloquinoline skeleton phosphine catalyst / ligand, characterized in that: The invention is prepared by using the axial chiral compound 1-(6-phenylindolo[1,2-a]quinolin-7-yl)naphthalen-2-ol as a key precursor. The hydroxyl group of the compound 1 and the carboxylic acid group of the 2-(arylphosphino or alkylphosphino)benzoic acid compound 2 undergo a condensation reaction under the condition of molecular sieve as a condensation agent. The synthesis route is as follows: 。 2. The method for preparing a chiral indoloquinoline skeleton phosphine catalyst / ligand according to claim 1, wherein: 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 obtained organic phase was dried over anhydrous sodium sulfate and then 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. A chiral indoloquinoline skeleton phosphine catalyst / ligand prepared by the method according to claim 1 or 2.

4. The use of the ligand according to claim 3, characterized in that: The ligand is used in asymmetric 1,4-conjugate addition reactions, and the amount of palladium catalyst used can be reduced to 0.2% without affecting the reaction efficiency and yield.

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