A novel chiral sulfinamide monophosphine ligand based on an oxanthracene skeleton, its preparation method and application

Abstract

This invention discloses a novel chiral sulfinamide monophosphine ligand based on an oxanthracene skeleton, its preparation method, and its application. The preparation method includes the following steps: (1) oxanthracene is subjected to a substitution reaction with RBr in the presence of sodium hydride and a solvent to obtain intermediate 1; (2) intermediate 1 is subjected to lithium halide exchange with butyllithium in the presence of a solvent, followed by the addition of a halogen to obtain intermediate 2; (3) intermediate 2 is subjected to halogen-metal exchange with isopropylmagnesium chloride in the presence of a solvent, followed by the addition of diphenylphosphine chloride to undergo a substitution reaction to obtain intermediate 3; (4) intermediate 3 is subjected to lithium halide exchange with butyllithium in the presence of a solvent, followed by the addition of a compound to react in the presence of a Lewis acid to obtain the chiral sulfinamide monophosphine ligand. The chiral sulfinamide monophosphine ligand prepared by this invention can be used to prepare chiral α-alkyl-α-benzyltetrahydronaphthone compounds with high yield and ee value.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a novel chiral sulfonamide monophosphine ligand based on xanthene skeleton and a preparation method and application thereof. BACKGROUND

[0002] Chirality is widely present in nature and is one of the basic properties of matter in nature. In living organisms, most biomolecules such as proteins, nucleotides and sugars are chiral molecules. Most of the organic molecules that constitute living organisms are chiral molecules. Some commonly used drugs and food additives in our life are also chiral compounds. Because chiral substances have chiral centers in their structures, the biochemical activities of two enantiomers are not the same, and some enantiomers even have completely opposite properties. Therefore, it is very important to obtain a single isomer of a chiral compound. Chiral compounds can be obtained by the following methods: separation of natural products, induction of substrates or chiral reagents, resolution of enantiomers and asymmetric catalytic synthesis. Among these methods, asymmetric catalytic synthesis has great advantages in economy and environmental protection, and has been the focus and frontier of research for decades.

[0003] Chiral phosphine-containing compounds play an important role in chiral catalysts or ligands and are widely used in transition metal-catalyzed and tertiary phosphine-catalyzed asymmetric reactions. As early as the 1960s, chemists began to study chiral phosphine-containing compounds, and by now a large number of chiral phosphine-containing compounds have been synthesized. However, the synthesis of enantiomers of many chiral phosphine-containing compounds is still a difficult problem. Most chiral phosphine-containing compounds have complex chiral skeletons and have different degrees of difficulty in some aspects, such as expensive raw materials, low yield and low conversion rate. Therefore, it is of great application prospect to find a system that is low in raw material cost, environmentally friendly, easy to modify and convenient for efficient synthesis. SUMMARY

[0004] The present application provides a novel chiral sulfonamide monophosphine ligand based on xanthene skeleton and a preparation method and application thereof. The novel chiral sulfonamide monophosphine ligand can be used as a chiral catalyst for preparing chiral alpha-alkyl-alpha-benzyl tetrahydronaphthalenone compounds, and the system has the advantages of high yield and high ee value in preparing chiral alpha-alkyl-alpha-benzyl tetrahydronaphthalenone compounds.

[0005] To solve the above technical problems, the present application provides the following technical solutions:

[0006] The present application provides a novel chiral sulfonamide monophosphine ligand based on xanthene skeleton, characterized in that the chiral sulfonamide monophosphine ligand has the following structural general formula:

[0007]

[0008] wherein R is C1-C9 alkyl or C7-C9 benzyl;

[0009] Ar is phenyl or substituted phenyl, and the substituent on the substituted phenyl is C1-C4 alkyl;

[0010] Ad is adamantyl, t Bu is tert-butyl.

[0011] Further, R can be methyl, n-hexyl, n-decyl, cyclohexylmethyl, 4-methylpentyl, 3-phenylpropyl or benzyl; Ar can be phenyl, 3,5-MePh, 2,4-MePh, 2,3-MePh, 2,5-MePh or 3,5- t Bu2Ph.

[0012] The second aspect of the present application provides a preparation method of the novel chiral sulfinamide monophosphine ligand based on the xanthene skeleton of the first aspect, comprising the following steps:

[0013] (1) substituting xanthene with RBr in the presence of sodium hydride and a solvent to obtain intermediate 1 shown in formula (I);

[0014] (2) substituting intermediate 1 prepared in step (1) with butyl lithium in the presence of a solvent, and then adding halogen to obtain intermediate 2 shown in formula (II);

[0015] (3) halogen-metal exchange reaction of intermediate 2 prepared in step (2) with isopropyl magnesium chloride in the presence of a solvent, and then substituting with diphenyl chlorophosphine to obtain intermediate 3 shown in formula (III);

[0016] (4) lithium halogen exchange reaction of intermediate 3 prepared in step (3) with butyl lithium in the presence of a solvent, and then reacting with a compound shown in formula (IV) in the presence of a Lewis acid to obtain the chiral sulfinamide monophosphine ligand;

[0017] The structures of the above formula (I)-(IV) are as follows:

[0018]

[0019] wherein R is C1-C9 alkyl or C7-C9 benzyl;

[0020] X is halogen;

[0021] Ar is phenyl or substituted phenyl, and the substituent on the substituted phenyl is C1-C4 alkyl;

[0022] Ad is adamantyl, t Bu is tert-butyl.

[0023] Further, in step (1), sodium hydride is first reacted with a solvent to obtain a new base, and then xanthene and RBr are added to perform a substitution reaction under the action of the new base to obtain intermediate 1.

[0024] Further, the reaction temperature of the above sodium hydride and solvent is preferably 25-100℃, more preferably 60-90℃, for example 60℃, 70℃, 80℃, 90℃, etc., and the reaction time is preferably 1-10h, for example 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, etc., more preferably 2-5h.

[0025] Further, in step (1), the reaction temperature of the substitution reaction is preferably 25-100℃, more preferably 25-30℃, and the reaction time is 1-10h, more preferably 1-3h.

[0026] Further, in step (1), the molar ratio of xanthene to RBr and sodium hydride is preferably 1:1-10:1-10, for example 1:3.4:2.3.

[0027] Further, in step (1), the solvent is preferably one or more of dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ketone, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, chloroform, n-hexane, dimethyl sulfoxide, more preferably dry tetrahydrofuran.

[0028] Further, in step (2), the molar ratio of intermediate 1 to butyllithium and halogen is preferably 1:1-10:1-10, for example 1:2.5:2.5.

[0029] Further, in step (2), the reaction temperature of the substitution reaction is preferably -78℃-50℃, more preferably 25-50℃, for example 50℃, and the reaction time is preferably 1-10h, more preferably 3-6h.

[0030] Further, in step (2), the reaction temperature of the halogen addition reaction is preferably -50℃-25℃, more preferably 10-30℃, for example 25℃, and the reaction time is 1-10h, more preferably 3-6h.

[0031] Further, in step (2), the butyllithium can be n-butyllithium, isobutyllithium or tert-butyllithium.

[0032] Further, in step (2), the solvent is preferably one or more of dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, chloroform, n-hexane, dimethyl sulfoxide, more preferably dry tetrahydrofuran.

[0033] Further, in step (3), the molar ratio of the intermediate 2 to isopropylmagnesium chloride, diphenylphosphine chloride is preferably 1:1-10:1-10, for example 1:1.1:1.

[0034] Further, in step (3), the reaction temperature of the halogen-metal exchange reaction is -50℃-25℃, more preferably -10-10℃, for example 0℃, and the reaction time is preferably 1-10h, more preferably 1-3h.

[0035] Further, in step (3), the reaction temperature of the substitution reaction is -50℃-25℃, more preferably -10-10℃, for example 0℃, and the reaction time is 1-10, more preferably 3-5h.

[0036] Further, in step (3), the solvent is preferably one or more of dry dichloromethane, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, benzene, chlorobenzene, fluorobenzene, chloroform, n-hexane, dimethyl sulfoxide, more preferably dry tetrahydrofuran.

[0037] Further, in step (4), the molar ratio of the intermediate 3 to butyllithium is preferably 1:1-10, for example 1:1.1; the butyllithium can be n-butyllithium, isobutyllithium or tert-butyllithium.

[0038] Further, in step (4), the reaction temperature of the lithium halogen exchange reaction is preferably -78℃-25℃, and the reaction time is preferably 1-10h, more preferably 1-3h.

[0039] Further, in step (4), the compound represented by formula (IV) is obtained by reacting the compound represented by formula (V) with the compound represented by formula (6) in the presence of a condensing agent and a solvent, wherein the structures of formula (V) and formula (VI) are as follows:

[0040]

[0041] Further, the condensing agent is preferably tetraethyl titanate, tetraisopropyl titanate or tetramethyl titanate.

[0042] Further, the molar ratio of the compound of formula (V) to the compound of formula (6) to the condensing agent is preferably 1:1-10:1-10, for example 1:1.2:1.5.

[0043] Further, the temperature of the reaction is preferably 50-100℃, more preferably 50-70℃, and the time of the reaction is preferably 1-10h, more preferably 5-8h.

[0044] Further, in step (4), the Lewis acid is preferably BF3·Et2O.

[0045] Further, in step (4), the molar ratio of the intermediate 3 to the compound of formula (IV) to the Lewis acid is preferably 1:1-10:1-10, for example 1:1.2:1.3.

[0046] Further, in step (4), the temperature of the reaction is preferably -78℃-25℃, and the time of the reaction is preferably 1-10h.

[0047] The third aspect of the present application provides an application of the novel chiral sulfinamide monophosphine ligand based on the xanthene skeleton as a chiral catalyst in the preparation of chiral α-alkyl-α-benzyl tetrahydronaphthalenone compounds, the chiral α-alkyl-α-benzyl tetrahydronaphthalenone compounds have the following general structure formula:

[0048]

[0049] In the formula, R1 is methyl or ethyl;

[0050] R2 is hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, 1-naphthyl or 2-naphthyl.

[0051] Further, the chiral sulfinamide monophosphine ligand is more preferably one of the following structures L1-L6:

[0052]

[0053] In the formula, Ad is adamantyl, n-Hex is n-hexyl, n-Dec is n-decyl, t Bu is tert-butyl.

[0054] Compared with the prior art, the present application has the following beneficial effects:

[0055] The application provides a novel chiral sulfonamide monophosphine ligand based on an oxygen heterocyclic skeleton and a preparation method thereof, and the novel chiral sulfonamide monophosphine ligand can be used as a chiral catalyst to prepare chiral alpha-alkyl-alpha-benzyl tetrahydronaphthalenone compounds, and the yield of the system for preparing the chiral alpha-alkyl-alpha-benzyl tetrahydronaphthalenone compounds can be up to 100%, and the ee value can be up to more than 99%. BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1 The yield and ee value of the chiral alpha-alkyl-alpha-benzyl tetrahydronaphthalenone compounds prepared by using different chiral ligands. DETAILED DESCRIPTION

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0058] The application will be further described with reference to the drawings and specific examples in order to better enable those skilled in the art to understand and practice the application, but the examples are not intended to limit the application.

[0059] Example 1

[0060] This example relates to the preparation of chiral sulfonamide monophosphine ligands L1-L6, and the structures of the compounds are as follows:

[0061]

[0062] For example, the preparation process of the chiral sulfonamide monophosphine ligand L3 is as follows:

[0063] (1) A dry 500 mL three-necked round bottom flask was prepared, and under a nitrogen atmosphere, sodium hydride (185.0 mmol, 3.7 equiv.) was added, a rubber stopper was inserted, and anhydrous dimethyl sulfoxide (DMSO, 70 mL) was added to the flask by syringe, and stirred at 70 °C for 2 hours, and then returned to room temperature. A 250 mL single-necked reaction flask was dried, and a nitrogen balloon was attached to the flask, and under a nitrogen atmosphere, xanthene (50.0 mmol, 1.0 equiv.) was added, a rubber stopper was inserted, and anhydrous DMSO (160 mL) was added to the flask by syringe, and stirred until completely dissolved, and the xanthene DMSO solution was added to the above-mentioned mixture of sodium hydride and DMSO that had been returned to room temperature, and stirred for 10 minutes, and then cyclohexylmethyl bromide (110.0 mmol, 2.2 equiv.) was slowly added by syringe pump while stirring, at which time the flask was slightly warm to the touch, and the rate of addition of the corresponding bromide was reduced. After the resulting mixture was stirred at room temperature for 1 hour, the reaction system was cooled to 0 °C by an ice water bath, and then slowly quenched with water, and extracted with diethyl ether three times, and the combined organic phase was dried over anhydrous magnesium sulfate, and then rotary evaporated. The crude product was dissolved in solvent (petroleum ether: dichloromethane = 2:1), and filtered through a large fritted funnel packed with silica gel, and then rotary evaporated, and recrystallized from anhydrous ethanol to obtain intermediate 1, which has the structure: The yield was 77%.

[0064] (2) Prepare a dry 1000 mL three-necked round-bottomed flask, add the intermediate 1 prepared in step (1) (100.0 mmol, 1.0 equiv.) under nitrogen atmosphere, plug the rubber stopper, and add anhydrous methyl-tert-butyl ether (100 mL) and dry N,N,N',N'-tetramethylethylenediamine (TMEDA, 75 mL) into the flask through a syringe. After stirring at 0 °C for 10 min, add n-BuLi (250.0 mmol, 2.5 equiv., 2.5 M n-BuLi / n-hexane) dropwise. The reaction system gradually changes from colorless and clear to red-brown. Then transfer the reaction system to 50 °C for 4 h, and then transfer it to -50 °C. Add anhydrous tetrahydrofuran (100 mL) and stir for 10 min. Dry another 200 mL single-necked flask, add I2 (250.0 mmol, 2.5 equiv.), plug the rubber stopper, and add anhydrous tetrahydrofuran (100 mL) into the flask through a syringe. Add a nitrogen balloon to the flask, and quickly stir the I2 to dissolve it. Slowly add the I2 tetrahydrofuran solution into the 1000 mL flask, and observe the state of the reaction solution. Avoid solidification of the reaction solution, otherwise the yield of the reaction will be affected. Then turn off the refrigeration, and stir at room temperature for not less than 4 h. Quench the reaction solution with saturated aqueous sodium thiosulfate solution, extract with ethyl acetate for 3 times, separate the liquid, dry the combined organic phase with anhydrous sodium sulfate, and spin dry. Dissolve the crude product with solvent (petroleum ether: dichloromethane = 2: 1), and obtain the intermediate 2 by beating with methanol. The structure is as follows: The yield is 73%.

[0065] (3) Prepare a dry 500 mL three-necked round-bottomed flask, add 1-adamantanecarboxaldehyde (82.0 mmol, 1.0 equiv.) and tert-butylsulfinamide (98.4 mmol, 1.2 equiv.) under nitrogen atmosphere, plug the rubber stopper, and add anhydrous tetrahydrofuran (200 mL) and tetraisopropyl titanate (123.0 mmol, 1.5 equiv.) into the flask through a syringe. Stir at 50 °C for 4 h. After the reaction is completed, pour the reaction system into a 1000 mL beaker, add saturated brine, silica gel, and stir uniformly with a glass rod. Filter the reaction solution through a super large sand core funnel, extract with ethyl acetate for 3 times, separate the liquid, dry the combined organic phase with anhydrous sodium sulfate, spin dry, and obtain the product by column chromatography The yield is 75%.

[0066] Prepare a dry 250 mL three-necked round-bottom flask. Add intermediate 2 (30.0 mmol, 1.0 equiv.) prepared in step (2) under a nitrogen atmosphere. Stopper the flask with a rubber stopper. Add anhydrous tetrahydrofuran (70 mL) to the flask using a syringe. Stir at 0 °C for 10 minutes. Add isopropyl magnesium chloride (33.0 mmol, 1.1 equiv., 2 M isopropyl magnesium chloride / tetrahydrofuran solution) dropwise to the reaction system using a syringe. Stir at 0 °C for 2 hours. Add diphenylphosphine chloride (30.0 mmol, 1.0 equiv.) dropwise and stir at 0 °C for more than 4 hours. Quench the reaction solution with saturated ammonium chloride aqueous solution. Extract three times with ethyl acetate. Separate the liquids. Dry the combined organic phases with anhydrous sodium sulfate and evaporate to dryness. Add 80 mL of petroleum ether and 6 mL of acetone to the crude product and stir at room temperature for at least 4 hours under nitrogen protection. A large amount of white solid, namely intermediate 3, precipitates out. The yield was 65%.

[0067] (4) Prepare a dry 250mL three-necked round-bottom flask. Add intermediate 3 (19.5mmol, 1.0equiv.) prepared in step (3) under a nitrogen atmosphere. Stopper the flask with a rubber stopper. Add anhydrous dichloromethane (77mL) to the flask using a syringe. Stir at -78℃ for 10 minutes, then add n-BuLi (21.5mmol, 1.1equiv., 2.5M n-BuLi / n-hexane solution) dropwise. Stir at -78℃ for 1 hour. Separately, dry a 50mL single-necked reaction flask. Add a nitrogen balloon to the side of the flask and add the solution under a nitrogen atmosphere. (23.4 mmol, 1.2 equiv.) The flask was stoppered with a rubber stopper, and anhydrous dichloromethane (20 mL) was added via syringe. After stirring at -78 °C for 10 minutes, boron trifluoride diethyl ether complex (25.4 mmol, 1.3 equiv.) was added dropwise. The mixture was then slowly added along the inner wall of a 250 mL three-necked round-bottom flask via syringe. The refrigerator was turned off, and the mixture was stirred overnight. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, separated, and dried over anhydrous sodium sulfate. Column chromatography (petroleum ether: ethyl acetate = 5:1) yielded the product, chiral sulfinamide monophosphine ligand L3. The product was characterized by NMR and mass spectrometry, and the results are as follows:

[0068] 1H NMR (400 MHz, CDC13) δ 7.36 - 7.31 (m, 7H), 7.25 (d, J = 10.4 Hz, 4H), 7.14 (dd, J = 7.9, 1.5 Hz, 1H), 6.94 (m, J = 20.8, 7.6 Hz, 2H), 6.84 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 7.4, 3.9 Hz, 1H), 4.65 (d, J = 8.9 Hz, 1H), 3.40 (d, J = 8.9 Hz, 1H), 1.99 - 1.81 (m, 10H), 1.58 (s, 6H), 1.41 (d, J = 11.6 Hz, 11H), 1.20 - 1.13 (m, 2H), 1.08 - 0.83 (m, 9H), 0.79 (s, 9H), 0.60 (dd, J = 22.1, 12.0 Hz, 3H).

[0069] 13 C NMR (101 MHz, CDC13) δ 134.68, 134.47, 133.64, 133.44, 131.77, 128.74, 128.72, 128.65, 128.61, 128.52, 128.45, 128.26, 128.01, 126.35, 126.00, 125.57, 125.24, 122.82, 121.49, 61.33, 55.66, 54.92, 54.18, 41.16, 38.12, 37.74, 37.71, 36.88, 34.82, 34.80, 34.70, 34.60, 34.53, 34.16, 28.52, 26.48, 26.41, 26.21, 26.15, 21.62.

[0070] 31 P NMR (162 MHz, CDC13) δ -17.16.

[0071] HRMS (ESI): calculated for [C 54 H 68 NO2PS][M+H] + : 826.1620, found 826.1637.

[0072] Preparation of chiral sulfonamide monophosphine ligand L1: the same as the preparation method of chiral sulfonamide monophosphine ligand L3 described above, only cyclohexylmethyl bromide in step (1) is replaced by n-hexyl bromide to prepare the product chiral sulfonamide monophosphine ligand L1. The product is characterized by nuclear magnetic resonance and mass spectrometry, and the characterization results are as follows:

[0073] 1H NMR (400 MHz, CDC13) δ 7.31 (d, J = 24.6 Hz, 11H), 7.19 (d, J = 7.5 Hz, 1H), 7.00 (ddd, J = 30.6, 15.4, 7.5 Hz, 3H), 6.53 (dd, J = 7.7, 3.9 Hz, 1H), 4.76 (d, J = 7.7 Hz, 1H), 3.49 (d, J = 7.8 Hz, 1H), 2.02 - 1.81 (m, 11H), 1.57 (q, J = 12.3 Hz, 6H), 1.42 (s, 4H), 1.13 (dq, J = 19.2, 12.1, 9.6 Hz, 12H), 0.89 (s, 11H), 0.81 (dt, J = 12.8, 6.8 Hz, 8H).

[0074] 13 C NMR (101 MHz, CDC13) δ 172.79, 134.21, 134.08, 134.02, 133.88, 131.72, 128.69, 128.59, 128.51, 128.41, 127.89, 127.04, 126.68, 124.40, 123.32, 122.08, 60.76, 55.69, 45.76, 45.11, 37.97, 37.81, 36.80, 31.66, 29.55, 28.41, 24.70, 22.46, 22.41, 21.86, 14.00.

[0075] 31 P NMR (162 MHz, CDC13) δ -17.50.

[0076] HRMS (ESI): calculated for [C 52 H 68 NO2PS][M+H] + : 802.1405, found 802.1427.

[0077] Preparation of chiral sulfonamide monophosphine ligand L2: the same as the preparation method of chiral sulfonamide monophosphine ligand L3 described above, only replace cyclohexylmethyl bromide in step (1) with decyl bromide, to prepare the product chiral sulfonamide monophosphine ligand L2. The product is characterized by nuclear magnetic resonance and mass spectrometry, and the characterization results are as follows:

[0078] 1H NMR (400 MHz, CDCI3) δ 7.40-7.15 (m, 12H), 7.07-6.87 (m, 3H), 6.51 (s, 1 H), 4.84-4.65 (m, 1 H), 3.46 (d, J = 7.8 Hz, 1 H), 1.88 (q, J = 13.4, 10.9 Hz, 10H), 1.55 (d, J = 10.7 Hz, 7H), 1.31 -1.03 (m, 30H), 0.86 (s, 19H).

[0079] 13 C NMR (101 MHz, CDCI3) δ 134.23, 134.05, 133.86, 131.70, 128.60, 128.51, 128.41, 127.91, 127.04, 126.64, 125.38, 124.40, 123.33, 122.09, 60.77, 55.69, 45.68, 42.64, 37.97, 37.80, 36.81, 31.90, 29.92, 29.61, 29.58, 29.48, 29.29, 29.24, 28.42, 24.96, 24.74, 22.67, 21.85, 14.10.

[0080] 31 P NMR (162 MHz, CDCI3) δ -17.45.

[0081] HRMS (ESI): calculated for [C 60 H 84 NO2PS][M+H] + : 914.3532, found 914.3546.

[0082] Preparation of chiral sulfmide monophosphine ligand L4: the same as the preparation method of chiral sulfmide monophosphine ligand L3 described above, only the cyclohexyl methyl bromide in step (1) is replaced by 1-bromo-4-methylpentane, and the product chiral sulfmide monophosphine ligand L4 is prepared. The product is characterized by nuclear magnetic resonance and mass spectrometry, and the characterization results are as follows:

[0083] 1H NMR (400 MHz, CDC13) δ 7.36 - 7.31 (m, 8 H), 7.31 - 7.25 (m, 3 H), 7.19 (dd, J = 7.8, 1.6 Hz, 1 H), 7.07 - 6.92 (m, 3 H), 6.53 (m, J = 7.4, 3.9, 1.5 Hz, 1 H), 4.78 (dd, J = 7.6, 1.1 Hz, 1 H), 3.49 (d, J = 7.6 Hz, 1 H), 2.00 - 1.80 (m, 10 H), 1.55 (q, J = 12.2 Hz, 6 H), 1.40 - 1.25 (m, 5 H), 1.09 - 0.81 (m, 17 H), 0.75 - 0.64 (m, 12 H).

[0084] 13 C NMR (101 MHz, CDC13) δ 149.12, 137.27, 136.89, 136.76, 134.16, 134.08, 133.96, 133.88, 131.80, 128.68, 128.58, 128.51, 128.49, 128.42, 127.82, 127.04, 126.74, 125.33, 125.18, 124.39, 123.33, 122.06, 60.73, 55.69, 46.42, 44.91, 42.74, 39.18, 39.11, 37.96, 37.82, 36.79, 28.39, 27.77, 27.65, 22.73, 22.56, 22.51, 22.44, 22.22, 21.86.

[0085] 31 P NMR (162 MHz, CDC13) δ -17.65.

[0086] HRMS (ESI): calculated for [C 52 H 68 NO2PS][M+H] + : 802.1406, found 802.1421.

[0087] Preparation of chiral sulfonamide monophosphine ligand L5: the same as the preparation method of chiral sulfonamide monophosphine ligand L3 described above, only the cyclohexylmethyl bromide in step (1) is replaced by 3-bromopropylbenzene to prepare the product chiral sulfonamide monophosphine ligand L5. The product is characterized by nuclear magnetic resonance and mass spectrometry, and the characterization results are as follows:

[0088] 1H NMR (400 MHz, CDCI3) δ 7.38 - 7.10 (m, 18H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.92 (s, 6H), 6.49 (dd, J = 7.6, 3.8 Hz, 1H), 4.70 (d, J = 7.7 Hz, 1H), 3.44 (d, J = 7.8 Hz, 1H), 2.41 (q, J = 7.1 Hz, 4H), 1.95 (q, J = 7.7 Hz, 5H), 1.84 (d, J = 7.8 Hz, 6H), 1.53 (q, J = 12.1 Hz, 6H), 1.39 - 1.34 (m, 3H), 1.27 (d, J = 9.1 Hz, 3H), 0.81 (s, 9H).

[0089] 13 C NMR (101 MHz, CDCI3) δ 142.07, 134.16, 133.96, 133.76, 131.96, 128.56, 128.43, 128.22, 128.15, 128.08, 126.99, 125.63, 124.77, 124.44, 123.47, 122.25, 55.65, 45.05, 44.77, 42.53, 37.83, 36.79, 35.84, 28.36, 26.28, 26.15, 21.81.

[0090] 31 P NMR (162 MHz, CDCI3) δ -17.54.

[0091] HRMS (ESI): calculated for [C 58 H 64 NO2PS][M+H] + : 870.1730, found 870.1722.

[0092] Preparation of chiral sulfonamide monophosphine ligand L6: the same as the preparation method of chiral sulfonamide monophosphine ligand L3 described above, only the cyclohexylmethyl bromide in step (1) is replaced by benzyl bromide, to prepare the product chiral sulfonamide monophosphine ligand L6. The product is characterized by nuclear magnetic resonance and mass spectrometry, and the characterization results are as follows:

[0093] 1H NMR (400 MHz, CDC13) δ 7.69 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 6.4 Hz, 2H), 7.22 (d, J = 6.4 Hz, 3H), 7.16 - 7.11 (m, 3H), 7.06 (t, J = 7.7 Hz, 2H), 6.91 (p, J = 7.6 Hz, 7H), 6.79 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 7.6 Hz, 2H), 6.50 (d, J = 7.8 Hz, 2H), 6.45 - 6.41 (m, 1H), 4.20 (d, J = 9.0 Hz, 1H), 3.62 (d, J = 13.6 Hz, 1H), 3.57 - 3.49 (m, 2H), 3.44 (d, J = 13.3 Hz, 1H), 3.25 (d, J = 9.0 Hz, 1H), 1.81 (s, 3H), 1.71 (s, 1H), 1.65 (d, J = 12.1 Hz, 3H), 1.61 - 1.44 (m, 7H), 1.30 (s, 4H), 1.02 (d, J = 12.2 Hz, 3H), 0.92 (s, 3H), 0.73 (s, 9H).

[0094] 13 C NMR (101 MHz, CDC13) δ 186.84, 154.77, 148.79, 137.65, 137.28, 134.71, 134.50, 133.12, 132.92, 132.23, 130.23, 130.19, 128.79, 128.69, 128.51, 128.44, 128.36, 128.24, 127.39, 127.23, 126.91, 126.30, 125.91, 125.82, 122.66, 121.34, 61.31, 55.52, 51.79, 50.27, 45.81, 37.67, 37.21, 36.72, 31.59, 28.33, 22.66, 21.69, 14.12.

[0095] 31 P NMR (162 MHz, CDC13) δ -16.29.

[0096] HRMS (ESI): calculated for [C 54 H 56 NO2PS][M+H] + : 814.0667, found 814.0697.

[0097] In addition to the preparation of the above-mentioned chiral sulfonamide monophosphine ligands L1-L6, the following chiral sulfonamide monophosphine ligands L7-L12 are prepared in the present application:

[0098]

[0099] Example 2

[0100] The above-mentioned chiral sulfonamide monophosphine ligands L1-L12 and the chiral ligand D1 (the structural formula is as follows: ) are respectively used to prepare chiral α-alkyl-α-benzyl tetrahydronaphthone 3aa, as shown in the following scheme: Figure 1 The specific preparation process is as follows:

[0101] A dry 10 mL sealed tube is taken, a magnetic stir bar of appropriate size is placed in the tube, and Pd2(dba)3 (0.005 mmol, 5 mol%) and the ligand (0.01 mmol, 10 mol%) are accurately weighed and added to the tube, and a bottle cap is screwed on (not tightly). Then, 3-4 times of air exchange is performed under nitrogen protection, so that the entire tube is in a nitrogen atmosphere. Nitrogen is passed, the bottle cap is opened, and the extracted toluene (1.0 mL) is added to the tube by using a syringe, and the bottle cap is tightly screwed. The stirring speed is adjusted, and stirring is performed at room temperature for 1 hour. The tube is then taken into a glove box, and sodium tert-butoxide (0.35 mmol, 3.5 equiv.) is accurately weighed and added to the tube, and then the compound shown in formula 1a (0.1 mmol, 1.0 equiv.) and the compound shown in formula 2a (0.3 mmol, 2.0 equiv.) are accurately weighed and added to the tube by using a microsyringe, and the bottle cap is tightly screwed. The stirring speed is adjusted, and stirring is performed at 0°C for 48 hours. The yield is determined by GC, and the ee value is determined by HPLC.

[0102] The yield and ee value of the α-alkyl-α-benzyl tetrahydronaphthone 3aa prepared by using the chiral sulfonamide monophosphine ligands L1-L12 and the chiral ligand D1 are shown in Table 1 below:

[0103] Table 1

[0104] Chiral ligand Yield (%) ee value (%) L1 78％ 89％ L2 95％ 88％ L3 91％ 89％ L4 90％ 88％ L5 83％ 89％ L6 92％ 88％ L7 100％ 85％ L8 100％ 79％ L9 100％ 81％ L10 51％ 80％ L11 32％ 81％ L12 29％ -64％ D1 Traces None

[0105] As can be seen from Table 1, the chiral ligands L1-L12 prepared in the present application can be used as chiral catalysts to prepare chiral α-alkyl-α-benzyl tetrahydronaphthone with high ee value and high yield. In particular, the chiral α-alkyl-α-benzyl tetrahydronaphthone prepared by using the chiral ligands L1-L6 as chiral ligands has an ee value of more than 88%. However, the chiral ligand D1 cannot be used as a chiral catalyst to prepare the chiral α-alkyl-α-benzyl tetrahydronaphthone 3aa.

[0106] The above-described embodiments are merely preferred examples of the application and do not limit the scope of the application. Any equivalent alternative or transformation of the application made by those skilled in the art based on the application is within the scope of the application. The scope of the application is defined by the claims.

Claims

1. Use of a novel chiral sulfinamide monophosphine ligand based on an oxanthrene skeleton as a chiral catalyst in the preparation of chiral α-alkyl-α-benzyltetralones, characterized in that, The raw material for preparing the chiral α-alkyl-α-benzyl tetrahydronaphthone compound is compound 1a and compound 2aa; The structures of the compound 1a and compound 2aa are as follows: ； The chiral α-alkyl-α-benzyl tetrahydronaphthone compound has the following structure: ； The chiral sulfonamide monophosphine ligand is one of the following structures L1-L6: 。

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