Preparation method of chiral α-alkyl-α-benzyl tetrahydronaphthone compounds

Abstract

The present invention discloses a preparation method of chiral α-alkyl-α-benzyl tetrahydronaphthone compounds, specifically discloses an asymmetric benzyl alkylation reaction of palladium-catalyzed α-alkyl-α-benzyl tetrahydronaphthone compounds with high enantioselectivity and high yield. By reacting α-alkyl tetrahydronaphthone and benzyl trifluoroacetate in the presence of a palladium catalyst, PC-Phos chiral ligand, a base reagent, and a solvent, α-alkyl-α-benzyl tetrahydronaphthone compounds with high enantioselectivity are obtained. The above preparation method has easily available raw materials, a wide substrate range, mild reaction conditions, and the yield can be as high as 100%. More importantly, the product has good enantioselectivity, and the ee value can be up to more than 99%, providing a simple and efficient way for the preparation of chiral α-alkyl-α-benzyl tetrahydronaphthone compounds.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a method for preparing chiral α-alkyl-α-benzyltetralone compounds. Background Art

[0002] Tetralone compounds are an important class of intermediates and have important applications in medicine, chemical industry, agriculture, new materials, polymers, etc. Chiral α-alkyl-α-benzyltetralone compounds are more commonly present in natural and unnatural products with biological activities.

[0003] Currently, the main methods for preparing chiral α-alkyltetralone compounds are: asymmetric alkylation of achiral enolate lithium salts mediated by chiral tetradentate ligands (Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Letters. 1999, 40, 2803 - 2806; Krein, D. M.; Lowary, T. L. In Encyclopedia of Reagents for Organic Synthesis (EROS), 2002, 1 - 4). Asymmetric allylic alkylation of α-alkyltetralone catalyzed by transition metal palladium (Trost, B. M.; Schroeder, G. M. Journal of the American Chemical Society. 1999, 121, 6759 - 6760. You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Organic Letters. 2001, 3, 149 - 151). Among them, although the asymmetric alkylation reaction of achiral enolate lithium salts mediated by chiral tetradentate ligands can achieve asymmetric benzylation, a large amount of transition metal catalyst must be used in the reaction process to react with the pre-formed enolate; and for the asymmetric allylic alkylation of α-alkyltetralone compounds catalyzed by transition metal palladium, since the alkylating reagent is limited to allylation, this method cannot be used to prepare α-alkyl-α-benzyltetralone compounds.

[0004] Based on this, there is an urgent need for a method for efficiently synthesizing chiral α-alkyl-α-benzyltetralone compounds. Summary of the Invention

[0005] The present invention provides a method for preparing chiral α-alkyl-α-benzyltetralone compounds. Using benzyl trifluoroacetate, a benzyl alkylating reagent with a simple benzene ring, as a raw material, under the catalysis of a palladium catalyst and a specific chiral ligand, α-asymmetric benzyl alkylation of α-alkyltetralone can be achieved. The above preparation method has easily available raw materials, mild reaction conditions, and high product yields and ee values.

[0006] To solve the above technical problems, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing a chiral α-alkyl-α-benzyltetralone compound, which is characterized in that a compound shown in Formula I is reacted with a compound shown in Formula II in the presence of a palladium catalyst, a chiral ligand, a base reagent and an organic solvent to obtain a chiral α-alkyl-α-benzyltetralone compound shown in Formula III;

[0008] The structures of Formulas I to III are as follows:

[0009]

[0010] wherein, R 1 is methyl or ethyl;

[0011] R 2 is hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; on the benzene ring connected to R 2 1-2 substituents may be present, and the substituents are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, substituted phenyl, 1-naphthyl, and 2-naphthyl;

[0012] The chiral ligand has the following general structural formula:

[0013]

[0014] wherein, R is an alkyl group of C1-C9 or a benzyl group of C7-C9;

[0015] Ar is phenyl or substituted phenyl, and the substituent on the substituted phenyl is an alkyl group of C1-C4;

[0016] Ad is adamantyl, t Bu is tert-butyl.

[0017] Further, the palladium catalyst and the chiral ligand are first added to a solvent and stirred at 20-30 °C for 1-1.5 h to obtain a catalyst solution, and then the base reagent, the compound shown in Formula I, and the compound shown in Formula II are added to the catalyst solution for reaction to obtain the chiral α-alkyl-α-benzyltetralone compound.

[0018] Further, the chiral ligand is preferably one or more of the compounds L1 to L12 shown in the following structures:

[0019] .

[0020] Further, the palladium catalyst is preferably one or more of tris(dibenzylideneacetone)dipalladium-chloroform adduct, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene palladium dichloride, allylpalladium(II) chloride dimer, (2,4-cyclopentadien-1-yl)(phenyl-2-propenyl)-palladium, bis(benzonitrile)palladium dichloride, palladium chloride, dichloro(norbornadiene)palladium(II), tris(dibenzylideneacetone)dipalladium, palladium tetrafluoroborate tetraacetonitrile, bis(3,5,3',5'-dimethoxydibenzylideneacetone), palladium trifluoroacetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(acetylacetonato)palladium, palladium acetate, bis(dibenzylideneacetone)palladium, palladium iodide, palladium bromide, di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium; more preferably palladium acetate.

[0021] Further, the base reagent is preferably one or more of sodium tert-butoxide, potassium tert-butoxide, potassium tert-amylate; more preferably potassium tert-butoxide.

[0022] Further, the solvent is preferably one or more of toluene, benzonitrile, mesitylene, chlorobenzene, o-xylene, p-xylene, n-hexane, cyclohexane, methylcyclohexane, tetrahydrofuran, ether, 1,4-dioxane, cyclopentyl methyl ether, trifluorotoluene, toluene, ethyl acetate, n-hexane, methyl tert-butyl ether, isopropyl ether, n-butyl ether; more preferably benzonitrile.

[0023] Further, the molar ratio of the compound shown in formula I to the compound shown in formula II in the feeding is preferably 1:2 - 2.5, such as 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, etc., including but not limited to the above-listed molar ratios of the feeding.

[0024] Further, the molar ratio of the compound shown in formula I to the palladium catalyst in the feeding is 1:0.05 - 1, such as 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, etc., including but not limited to the above-listed molar ratios of the feeding.

[0025] Further, the molar ratio of the compound shown in formula I to the base reagent in the feeding is 1:2 - 5, such as 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc., including but not limited to the above-listed molar ratios of the feeding.

[0026] Further, the molar ratio of the palladium catalyst to the chiral ligand in the feed is 1:2 - 2.5, such as 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, etc., including but not limited to the molar ratios listed above.

[0027] Further, the reaction is carried out under an inert atmosphere, such as nitrogen, argon, etc., including but not limited to the gas types listed above.

[0028] Further, the reaction temperature of the reaction is -20 - 100 °C, such as -20 °C, -15 °C, -10 °C, -5 °C, 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, etc., including but not limited to the temperature values listed above.

[0029] Further, the reaction time of the reaction is not less than 48 h, and more preferably 48 - 72 h.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] The present invention provides a method for preparing chiral α-alkyl-α-benzyltetralone compounds. Using benzyl alkylating agent benzyl trifluoroacetate with a simple benzene ring as the reaction raw material, under the catalysis of a palladium catalyst and a specific chiral ligand, α-asymmetric benzyl alkylation of α-alkyltetralone can be achieved, and the product obtained by this preparation method has a high yield, up to 100%, and a product with an ee value of over 99% can be obtained by adjusting the reaction temperature. Specific Embodiments

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this invention belongs. The terms used in the description of the present invention herein are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0033] The following further illustrates the present invention with specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the examples given are not intended to limit the present invention.

[0034] Example 1

[0035] This example relates to the preparation of chiral ligands L1 - L12, and the structures of the compounds are shown as follows:

[0036]

[0037] Taking the preparation of chiral ligand L9 as an example, its specific preparation process is as follows:

[0038] (1) Prepare a dry 500 mL three-necked round-bottom flask. Under a nitrogen atmosphere, add sodium hydride (185.0 mmol, 3.7 equiv.), plug in a rubber stopper, and add anhydrous dimethyl sulfoxide (DMSO, 70 mL) to the flask through a syringe. Stir at 70 °C for 2 hours and then return to room temperature. Dry a 250 mL single-neck reaction flask, add a nitrogen balloon to the side neck of the flask, add xanthene (50.0 mmol, 1.0 equiv.) under a nitrogen atmosphere, plug in a rubber stopper, and add anhydrous DMSO (160 mL) to the flask through a syringe. Stir until completely dissolved. At room temperature, add the DMSO solution of xanthene to the mixture of sodium hydride and DMSO that has returned to room temperature, stir for 10 minutes, and then slowly dropwise add cyclohexylmethyl bromide (110.0 mmol, 2.2 equiv.) with a syringe pump while stirring. At this time, touch the wall of the flask, which is slightly warm, and reduce the dropping rate of the corresponding bromide. After the resulting mixture is stirred at room temperature for 1 hour, cool the reaction system to 0 °C by means of an ice-water bath, then slowly add water to quench the reaction solution, extract with diethyl ether 3 times, separate the layers, dry the combined organic phases with anhydrous magnesium sulfate, and rotary evaporate. Dissolve the crude product in a solvent (petroleum ether:dichloromethane = 2:1), filter through a large sintered glass funnel filled with silica gel, rotary evaporate, and recrystallize with absolute ethanol to obtain intermediate 1, whose structure is: The yield is 77%.

[0039] (2) Prepare a dry 1000 mL three-necked round-bottom flask. Under a nitrogen atmosphere, add intermediate 1 prepared in step (1) (100.0 mmol, 1.0 equiv.), plug in a rubber stopper, and add anhydrous methyl tert-butyl ether (100 mL) and dry N,N,N',N'-tetramethylethylenediamine (TMEDA, 75 mL) to the flask through syringes respectively. After stirring at 0 °C for 10 minutes, add n-BuLi (250.0 mmol, 2.5 equiv., 2.5 M n-BuLi / n-hexane). The reaction system gradually changes from colorless and clear to reddish-brown. Subsequently, transfer it to 50 °C for reaction for 4 hours, then transfer the reaction system to -50 °C, add anhydrous tetrahydrofuran (100 mL), and stir for 10 minutes. Additionally, dry a 200 mL single-neck reaction flask, add 2 iodine 2 element (250.0 mmol, 2.5 equiv.), plug in a rubber stopper, add anhydrous tetrahydrofuran (100 mL) to the flask through a syringe, add a nitrogen balloon to the side neck of the flask, and quickly stir with a magnetic stirrer to dissolve 2Transfer the tetrahydrofuran solution to a 1000 mL flask. While observing the state of the reaction solution in the flask, take care to avoid solidification of the reaction solution, as this will affect the reaction yield. Subsequently, turn off the cooling and transfer to room temperature for stirring for at least 4 hours. Quench the reaction solution with saturated aqueous sodium thiosulfate, extract 3 times with ethyl acetate, separate the layers, dry the combined organic phases with anhydrous sodium sulfate, and rotary evaporate. Dissolve the crude product in a solvent (petroleum ether:dichloromethane = 2:1), and slurry with methanol to obtain Intermediate 2, whose structure is: The yield was 73%.

[0040] (3) Prepare a dry 500 mL three-necked round-bottomed flask. Under a nitrogen atmosphere, add 1-adamantanecarboxaldehyde (82.0 mmol, 1.0 equiv.) and tert-butanesulfinamide (98.4 mmol, 1.2 equiv.). Plug with a rubber stopper, and add anhydrous tetrahydrofuran (200 mL) and titanium tetraisopropoxide (123.0 mmol, 1.5 equiv.) to the flask through syringes respectively. Stir at 50 °C for 4 hours. After the reaction is completed, pour the reaction system into a 1000 mL beaker, add saturated brine and silica gel, stir evenly with a glass rod, filter the reaction solution through a large sintered glass funnel, wash 4 - 5 times with ethyl acetate, extract 3 times with ethyl acetate, separate the layers, dry the combined organic phases with anhydrous sodium sulfate, rotary evaporate, and obtain the product by column chromatography The yield was 75%.

[0041] Prepare a dry 250 mL three-necked round-bottomed flask. Under a nitrogen atmosphere, add Intermediate 2 prepared in step (2) (30.0 mmol, 1.0 equiv.). Plug with a rubber stopper, and add anhydrous tetrahydrofuran (70 mL) to the flask through a syringe. After stirring at 0 °C for 10 minutes, add isopropylmagnesium chloride (33.0 mmol, 1.1 equiv., 2 M isopropylmagnesium chloride / tetrahydrofuran solution) dropwise to the reaction system through a syringe. Stir at 0 °C for 2 hours, add diphenylphosphine chloride (30.0 mmol, 1.0 equiv.), and stir at 0 °C for more than 4 hours. Quench the reaction solution with saturated aqueous ammonium chloride, extract 3 times with ethyl acetate, separate the layers, dry the combined organic phases with anhydrous sodium sulfate, and rotary evaporate. Add 80 mL of petroleum ether and 6 mL of acetone to the crude product, and stir at room temperature under nitrogen protection for at least 4 hours), then a large amount of white solid precipitates, which is Intermediate 3 The yield was 65%.

[0042] (4) Prepare a dry 250 mL three-necked round-bottomed flask. Under a nitrogen atmosphere, add the intermediate 3 prepared in step (3) (19.5 mmol, 1.0 equiv.). Plug with a rubber stopper, and add anhydrous dichloromethane (77 mL) to the flask through a syringe. After stirring at -78 °C for 10 minutes, add n-BuLi (21.5 mmol, 1.1 equiv., 2.5 M n-BuLi / n-hexane solution) dropwise, and stir at -78 °C for 1 hour. Additionally, dry a 50 mL single-necked reaction flask, add a nitrogen balloon to the side port of the flask, and add (23.4 mmol, 1.2 equiv.) under a nitrogen atmosphere. Plug with a rubber stopper, add anhydrous dichloromethane (20 mL) to the flask through a syringe. After stirring at -78 °C for 10 minutes, add boron trifluoride diethyl ether complex (25.4 mmol, 1.3 equiv.) dropwise. Slowly add the mixture to the 250 mL three-necked round-bottomed flask along the inner wall through a syringe, turn off the cooling, and stir overnight. After the reaction is completed, quench the reaction solution with saturated ammonium chloride aqueous solution, extract 3 times with ethyl acetate, separate the layers, dry the combined organic phases with anhydrous sodium sulfate, and evaporate to dryness. Column chromatography (petroleum ether:ethyl acetate = 5:1) gives the product chiral ligand L9. Characterize the product by NMR and mass spectrometry, and the characterization results are as follows:

[0043] 1 H NMR(400MHz,CDCl 3 )δ7.36 - 7.31(m,7H),7.25(d,J = 10.4Hz,4H),7.14(dd,J = 7.9,1.5Hz,1H),6.94(m,J = 20.8,7.6Hz,2H),6.84(d,J = 7.5Hz,1H),6.48(dd,J = 7.4,3.9Hz,1H),4.65(d,J = 8.9Hz,1H),3.40(d,J = 8.9Hz,1H),1.99 - 1.81(m,10H),1.58(s,6H),1.41(d,J = 11.6Hz,11H),1.20 - 1.13(m,2H),1.08 - 0.83(m,9H),0.79(s,9H),0.60(dd,J = 22.1,12.0Hz,3H).

[0044] 13 C NMR(101MHz,CDCl 3)δ134.68, 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.

[0045] 31 PNMR(162MHz, CDCl 3 )δ - 17.16.

[0046] HRMS(ESI): calculated for [C 54 H 68 NO 2 PS][M + H] + : 826.1620, found 826.1637.

[0047] The preparation methods of chiral ligands L1 - L8 and L10 - L12 are the same as that of the above - mentioned chiral ligand L9.

[0048] Example 2

[0049] This example relates to the preparation of chiral α - alkyl - α - benzyl tetrahydronaphthalenone 3aa, and its structure is as follows:[[]]END]]

[0050] The specific preparation process is as follows:

[0051] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium catalyst (0.005 mmol, 5 mol%), chiral ligand (0.01 mmol, 10 mol%) and add them into the sealed tube. Screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and filling operations to make the whole sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted solvent (1.0 mL) into the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh the base reagent (0.35 mmol, 3.5 equiv.) and add it into the sealed tube. Then accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and benzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe and add them into the sealed tube. Tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter. The obtained filtrate is first dried by rotary evaporation of dichloromethane and ethyl acetate, and then the remaining liquid is transferred to a bottle as small as possible. After inserting a cotton plug into the tap, while evenly heating the bottle body with a hair dryer, pump for about 10 minutes with an oil pump until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. Measure the yield by GC and measure the ee value by HPLC.

[0052] (1) Effects of different palladium catalysts on the reaction yield and ee value

[0053] In the above preparation process, the chiral ligand is L1, the solvent is toluene, the base reagent is sodium tert - butoxide, and the reaction is stirred at 75 °C for 48 hours. The effects of different palladium catalysts on the reaction yield and ee are studied, and the results are shown in Table 1:

[0054] Table 1

[0055]

[0056]

[0057] As can be seen from Table 1, under the condition that other conditions are the same, when the palladium catalyst is palladium acetate, the reaction rate is relatively fast and the ee value of the prepared product is the highest.

[0058] (2) Effects of different solvents on the reaction yield and ee value

[0059] In the above preparation process, the palladium catalyst is palladium acetate, the chiral ligand is L1, the base reagent is sodium tert - butoxide, and the reaction is stirred at 75 °C for 48 hours. The effects of different solvents on the reaction yield and ee are studied, and the results are shown in Table 2:

[0060] Table 2

[0061]

[0062]

[0063] As can be seen from Table 2, under the condition that other conditions are the same, when the solvent is benzonitrile, the ee value of the product is the highest.

[0064] (3) Effects of different base reagents on the reaction yield and ee value

[0065] In the above preparation process, the palladium catalyst is palladium acetate, the chiral ligand is L1, the solvent is benzonitrile, and the reaction is stirred at 75 °C for 48 hours. The effects of different base reagents on the reaction yield and ee are studied, and the results are shown in Table 3:

[0066] Table 3

[0067]

[0068]

[0069] Potassium tert-butoxide a : React at 25 °C for 48 hours; Potassium tert-butoxide b : React at 0 °C for 48 hours.

[0070] As can be seen from Table 3, under the condition that other conditions are the same, when the base reagent is potassium tert-butoxide and the reaction is stirred at 0 °C for 48 hours, the product yield can reach as high as 98%, and the ee value of the product can reach 85%.

[0071] (4) Effects of different chiral ligands on the reaction yield and ee value

[0072] In the above preparation process, the palladium catalyst is palladium acetate, the solvent is benzonitrile, the base reagent is potassium tert-butoxide, and the reaction is stirred at 0 °C for 48 hours. The effects of different chiral ligands on the reaction yield and ee are studied, and the results are shown in Table 4:

[0073] Table 4

[0074]

[0075]

[0076]

[0077] As can be seen from Table 4, under the condition that other conditions are the same, when any of the compounds L1-L3 is used as the chiral ligand, the reaction is stirred at 0 °C for 48 hours, and the product yield can reach as high as 100%. Among them, the ee value of the product prepared with the chiral ligand L1 as the chiral catalyst can reach 85%. When any of the compounds L6-L12 is used as the chiral catalyst, the ee value of the obtained product is not less than 88%. When the analog D1 is used as the chiral catalyst, only a very small amount of chiral α-alkyl-α-benzyltetrahydronaphthalenone 3aa is obtained in the reaction system after stirring for 48 hours.

[0078] The product prepared above was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0079] 1 1H NMR (400 MHz, CDCl 3 3) δ 8.08 (d, J = 6.4 Hz, 1H), 7.43 (t, J = 6.7 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 (d, J = 6.8 Hz, 2H), 7.17 (dd, J = 19.0, 6.8 Hz, 4H), 3.09 (d, J = 13.4 Hz, 1H), 2.97 (t, J = 5.9 Hz, 2H), 2.84 (d, J = 13.4 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.83 (m, J = 13.7, 5.8 Hz, 1H), 1.16 (s, 3H).

[0080] 13 13C NMR (101 MHz, CDCl 3 3) δ 201.99, 143.23, 137.69, 133.15, 131.80, 130.75, 128.70, 128.12, 127.98, 126.72, 126.33, 45.84, 42.74, 33.07, 25.48, 22.38.

[0081] HRMS (ESI): Calcd for C 18 15 18 H + 17ONa [M + Na]

[0082] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 30.8 min, t R(Minimum) = 35.3 min.

[0083] Example 3

[0084] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ab, and its structure is shown as follows:

[0085] The specific preparation process is as follows:

[0086] Take a dry 10 mL sealed tube, put in a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), and add them to the sealed tube. Screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and replacement operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, and use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube. Screw on the bottle cap tightly. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert-butoxide (0.35 mmol, 3.5 equiv.) and add it to the sealed tube. Then accurately measure α-methyltetralone (0.1 mmol, 1.0 equiv.) and 4-phenylbenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe and add them to the sealed tube. Screw on the bottle cap tightly. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter. The obtained filtrate is first rotary-evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, and then the remaining liquid is transferred to a bottle as small as possible. After plugging the tap with cotton, while evenly heating the bottle body with a hair dryer, pump with an oil pump for about 10 minutes until the solvent is completely dried, and then perform column chromatography (n-hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 89%, and the ee value measured by HPLC is greater than 99%.

[0087] Perform 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations on the prepared product, and the characterization results are as follows:

[0088] 1 1H NMR (400 MHz, CDCl 3)δ8.15(d, J = 6.4Hz, 1H), 7.62(d, J = 7.0Hz, 2H), 7.54(d, J = 8.2Hz, 2H), 7.51 - 7.43(m, 3H), 7.36(t, J = 6.6Hz, 2H), 7.29 - 7.25(m, 3H), 3.20(d, J = 13.4Hz, 1H), 3.05(t, J = 6.4Hz, 2H), 2.94(d, J = 13.4Hz, 1H), 2.13 - 2.06(m, 1H), 1.93(m, J = 13.7, 5.7Hz, 1H), 1.26(s, 3H).

[0089] 13 C NMR(101MHz, CDCl 3 )δ201.98, 143.24, 140.96, 139.20, 136.84, 131.80, 131.17, 128.76, 128.72, 128.15, 127.13, 127.01, 126.74, 126.68, 45.94, 42.44, 25.51, 22.42.

[0090] HRMS(ESI): Calcd for C 24 H 22 ONa[M + Na] + : 349.4285; Found 349.4278.

[0091] HPLC conditions: Daicel CHIRALPAK AS - H and AD - H (n - hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 40.6 min, t R (min) = 46.3 min.

[0092] Example 4

[0093] This example relates to the preparation of chiral α - alkyl - α - benzyltetralone 3ac, the structure of which is shown below:

[0094] The specific preparation process is as follows:

[0095] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%), chiral ligand L9 (0.01 mmol, 10 mol%) and add them into the sealed tube, then screw on the bottle cap (do not tighten it). Then, under nitrogen protection, perform 3 - 4 evacuation and replacement operations to make the whole sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) into the sealed tube, and screw on the bottle cap tightly. Adjust the stirring speed and stir at room temperature for 1 hour. Then take the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.) and add it into the sealed tube. Then accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 4 - methylbenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe and add them into the sealed tube, and screw on the bottle cap tightly. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter it. The obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, then transfer the remaining liquid to a bottle as small as possible. After stuffing the stopper with cotton, while evenly heating the bottle body with a hair dryer, pump for about 10 minutes with an oil pump until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 89%, and the ee value measured by HPLC is greater than 99%.

[0096] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0097] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J = 7.9 Hz, 1H), 7.43 (m, J = 7.4, 1.5 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.07 - 7.01 (m, 4H), 3.05 (d, J = 13.5 Hz, 1H), 2.96 (q, J = 5.6 Hz, 2H), 2.80 (d, J = 13.5 Hz, 1H), 2.29 (s, 3H), 1.98 (m, J = 13.7, 8.1, 5.7 Hz, 1H), 1.85 - 1.79 (m, 1H), 1.15 (s, 3H).

[0098] 13 13C NMR (101 MHz, CDCl 3)δ202.11,143.26,135.80,134.51,133.11,131.84,130.62,128.70,128.11,126.69,45.84,42.25,33.07,25.50,22.36,21.05.

[0099] HRMS(ESI):Calcd for C 19 H 20 ONa[M+Na] + :287.3576;Found 287.3583.

[0100] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 28.4 min, t R (min) = 31.2 min.

[0101] Example 5

[0102] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ad, and its structure is shown as follows:

[0103] The specific preparation process is as follows:

[0104] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them to the sealed tube, and screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and filling operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.), add it to the sealed tube, and accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 3 - methoxybenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe, and add them to the sealed tube, then tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter it. The obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, then transfer the remaining liquid to a bottle as small as possible. After plugging the tap with cotton, while evenly heating the bottle body with a hair dryer, pump for about 10 minutes with an oil pump until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 91%, and the ee value measured by HPLC is 86%.

[0105] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0106] 1 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.3 Hz, 1H), 7.48 (m, J = 7.5, 1.5 Hz, 1H), 7.34 (t, J = 7.0 Hz, 1H), 7.25 - 7.18 (m, 2H), 6.80 - 6.74 (m, 3H), 3.80 (s, 3H), 3.14 (d, J = 13.3 Hz, 1H), 3.01 (t, J = 6.4 Hz, 2H), 2.86 (d, J = 13.4 Hz, 1H), 2.04 (m, J = 13.9, 6.9 Hz, 1H), 1.88 (m, J = 13.7, 5.7 Hz, 1H), 1.22 (s, 3H).

[0107] 13 13C NMR (101 MHz, CDCl 3)δ201.99,159.27,143.23,133.15,131.81,128.86,128.70,128.09,126.70,123.21,116.59,111.55,55.13,45.84,42.86,33.10,25.47,22.48.

[0108] HRMS(ESI):Calcd for C 19 H 20 O 2 Na[M+Na] + :303.3576;Found 303.3589.

[0109] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 43.1 min, t R (min) = 46.9 min.

[0110] Example 6

[0111] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ae, the structure of which is shown below:

[0112] The specific preparation process is as follows:

[0113] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them into the sealed tube, and screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and filling operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) into the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.), add it into the sealed tube, and accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 2 - methylbenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe, add them into the sealed tube, and tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter it. The obtained filtrate is first dried by rotary evaporation of dichloromethane and ethyl acetate, and then the remaining liquid is transferred to a bottle as small as possible. After plugging the tap with cotton, while evenly heating the bottle body with a hair dryer, pump with an oil pump for about 10 minutes until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 94%, and the ee value measured by HPLC is 86%.

[0114] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0115] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 6.4 Hz, 1H), 7.43 (m, J = 7.4, 1.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.13 - 7.10 (m, 1H), 7.09 - 7.05 (m, 3H), 3.07 (d, J = 3.0 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H), 2.30 (s, 3H), 2.07 (m, J = 14.0, 7.1 Hz, 1H), 1.90 (m, J = 13.6, 5.6 Hz, 1H), 1.17 (s, 3H).

[0116] 1313C NMR (101 MHz, CDCl3) δ 137.35, 136.34, 133.15, 131.89, 131.30, 130.51, 128.69, 128.17, 126.75, 126.34, 125.50, 46.74, 38.57, 33.53, 25.43, 22.30, 20.59.

[0117] HRMS (ESI): C 19 H 20 ONa [M+Na] + : 287.3576; Found 287.3564.

[0118] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 25.1 min, t R (min) = 38.6 min.

[0119] Example 7

[0120] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3af, the structure of which is shown below:

[0121] The specific preparation process is as follows:

[0122] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them to the sealed tube, and screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and filling operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.), add it to the sealed tube, and then accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 2 - chlorobenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe and add them to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter, and the obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, then transfer the remaining liquid to a bottle as small as possible. After plugging the tap with cotton, while evenly heating the bottle body with a hair dryer, pump with an oil pump for about 10 minutes until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 53%, and the ee value measured by HPLC is 80%.

[0123] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0124] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 6.4 Hz, 1H), 7.48 (m, J = 7.4, 1.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.26 - 7.21 (m, 2H), 7.18 - 7.12 (m, 2H), 3.34 - 3.24 (m, 2H), 3.04 - 2.94 (m, 2H), 2.12 (m, J = 14.4, 9.0, 5.7 Hz, 1H), 2.02 (m, J = 13.7, 5.4 Hz, 1H), 1.26 (s, 3H).

[0125] 13 13C NMR (101 MHz, CDCl 3)δ201.66,143.19,136.09,135.36,133.16,132.58,131.77,129.56,128.65,128.16,127.68,126.69,126.42,46.88,38.83,33.16,25.37,22.38.

[0126] HRMS(ESI):Calcd for C 18 H 17 ClONa[M+Na] + :307.7728;Found 307.7735.

[0127] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (maximum) = 24.9 min, t R (minimum) = 32.7 min.

[0128] Example 8

[0129] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ag, the structure of which is shown below:

[0130] The specific preparation process is as follows:

[0131] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them to the sealed tube, and screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and replacement operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.) and add it to the sealed tube. Then accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 1 - naphthyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe and add them to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter it. The obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, then transfer the remaining liquid to a bottle as small as possible. After plugging the extraction head with cotton, while evenly heating the bottle body with a hair dryer, pump with an oil pump for about 10 minutes until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 91%, and the ee value measured by HPLC is 80%.

[0132] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0133] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, J = 6.4 Hz, 1H), 7.48 (m, J = 7.4, 1.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.26 - 7.21 (m, 2H), 7.18 - 7.12 (m, 2H), 3.34 - 3.24 (m, 2H), 3.04 - 2.94 (m, 2H), 2.12 (m, J = 14.4, 9.0, 5.7 Hz, 1H), 2.02 (m, J = 13.7, 5.4 Hz, 1H), 1.26 (s, 3H).

[0134] 13 13C NMR (101 MHz, CDCl 3)δ201.66,143.19,136.09,135.36,133.16,132.58,131.77,129.56,128.65,128.16,127.68,126.69,126.42,46.88,38.83,33.16,25.37,22.38.

[0135] HRMS(ESI):Calcd for C 18 H 17 ClONa[M+Na] + :307.7728;Found 307.7735.

[0136] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 45.3 min, t R (min) = 56.3 min.

[0137] Example 9

[0138] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ah, whose structure is shown as follows:

[0139] The specific preparation process is as follows:

[0140] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them to the sealed tube, and screw on the bottle cap (do not tighten it). Then, under nitrogen protection, perform 3 - 4 evacuation and filling operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.), add it to the sealed tube, and accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 3 - methylbenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a micro - syringe and add them to the sealed tube, then tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter it. The obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, then transfer the remaining liquid to a bottle as small as possible. After stuffing the tap with cotton, while evenly heating the bottle body with a hair dryer, pump with an oil pump for about 10 minutes until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 98%, and the ee value measured by HPLC is 88%.

[0141] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0142] 1 1H NMR (400 MHz, CDCl 3 3) δ 8.14 (d, J = 6.4 Hz, 1H), 7.50 (m, J = 7.4, 1.5 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.04 (dd, J = 21.8, 9.1 Hz, 3H), 3.12 (d, J = 13.4 Hz, 1H), 3.06 - 2.99 (m, 2H), 2.87 (d, J = 13.4 Hz, 1H), 2.37 (s, 3H), 2.05 (m, J = 13.8, 8.0, 5.9 Hz, 1H), 1.89 (m, J = 13.7, 5.6 Hz, 1H), 1.22 (s, 3H).

[0143] 13 13C NMR (101 MHz, CDCl 3)δ202.08,143.26,137.61,137.44,133.12,131.85,131.56,128.70,128.11,127.86,127.81,127.09,126.70,45.79,42.63,33.07,25.50,22.39,21.49.

[0144] HRMS(ESI):Calcd for C 19 H 20 ONa[M+Na] + :287.3576;Found 287.3569.

[0145] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 23.6 min, t R (min) = 26.6 min.

[0146] Example 10

[0147] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ai, whose structure is shown as follows:

[0148] The specific preparation process is as follows:

[0149] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them to the sealed tube, and screw on the bottle cap (do not tighten it). Then, under nitrogen protection, perform 3 - 4 evacuation and replacement operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.) and add it to the sealed tube. Then accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 3 - fluorobenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe and add them to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter. The obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, and then transfer the remaining liquid to a bottle as small as possible. After plugging the tap with cotton, while evenly heating the bottle body with a hair dryer, pump with an oil pump for about 10 minutes until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 90%, and the ee value measured by HPLC is 89%.

[0150] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0151] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.19 (dd, J = 10.0, 7.7 Hz, 2H), 6.89 (dd, J = 21.1, 8.1 Hz, 3H), 3.13 (d, J = 13.4 Hz, 1H), 3.01 - 2.94 (m, 2H), 2.82 (d, J = 13.4 Hz, 1H), 1.99 (m, J = 14.2, 8.5, 5.9 Hz, 1H), 1.84 (m, J = 13.7, 5.5 Hz, 1H), 1.17 (s, 3H).

[0152] 13 13C NMR (101 MHz, CDCl 3)δ 201.57, 163.75, 161.32, 143.10, 131.66, 129.34, 129.26, 128.70, 128.14, 126.77, 126.44, 126.41, 117.59, 117.39, 113.33, 113.12, 45.83, 42.65, 33.07, 25.40, 22.38.

[0153] 19 19F NMR (376 MHz, CDCl3) δ -113.92 (s).

[0154] HRMS (ESI): Calcd for C 18 H 17 FONa [M+Na] + : 291.3212; Found 291.3201.

[0155] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 26.8 min, t R (min) = 30.7 min.

[0156] Example 11

[0157] This example relates to the preparation of chiral α-alkyl-α-benzyltetralone 3ai, whose structure is shown as follows:

[0158] The specific preparation process is as follows:

[0159] Take a dry 10 mL sealed tube, place a magnetic stir bar of appropriate size, accurately weigh palladium acetate (0.005 mmol, 5 mol%) and chiral ligand L9 (0.01 mmol, 10 mol%), add them to the sealed tube, and screw on the bottle cap (do not tighten). Then, under nitrogen protection, perform 3 - 4 evacuation and filling operations to make the entire sealed tube in a nitrogen atmosphere. Pass nitrogen, open the bottle cap, use a syringe to add the extracted benzonitrile (1.0 mL) to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and stir at room temperature for 1 hour. Then bring the sealed tube into the glove box, accurately weigh potassium tert - butoxide (0.35 mmol, 3.5 equiv.), add it to the sealed tube, and then accurately measure α - methyltetralone (0.1 mmol, 1.0 equiv.) and 4 - fluorobenzyl trifluoroacetate (0.3 mmol, 2.0 equiv.) with a microsyringe, add them to the sealed tube, and tighten the bottle cap. Adjust the stirring speed and carry out the stirring reaction. After the reaction is completed, filter it. The obtained filtrate is first rotary - evaporated to dryness for dichloromethane and ethyl acetate using a rotary evaporator, then transfer the remaining liquid to the smallest possible bottle. After plugging the tap with cotton, while evenly heating the bottle body with a hair dryer, pump for about 10 minutes with an oil pump until the solvent is completely dried, and then perform column chromatography (n - hexane:ethyl acetate = 1000:1) to separate the product. The yield measured by GC is 92%, and the ee value measured by HPLC is 78%.

[0160] The prepared product was subjected to 1 1H NMR, 13 13C NMR, HRMS and HPLC characterizations, and the characterization results are as follows:

[0161] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 8.2 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.96 (t, J = 8.7 Hz, 2H), 3.13 (d, J = 13.6 Hz, 1H), 3.01 (t, J = 6.4 Hz, 2H), 2.84 (d, J = 13.6 Hz, 1H), 2.02 (m, J = 14.0, 7.0 Hz, 1H), 1.87 (m, J = 13.6, 5.7 Hz, 1H), 1.19 (s, 3H).

[0162] 13 13C NMR (101 MHz, CDCl 3)δ 201.75, 162.89, 160.46, 143.13, 133.36, 133.33, 133.21, 132.08, 132.01, 131.72, 128.70, 128.08, 126.75, 114.86, 114.65, 42.03, 33.06, 22.37.

[0163] 19 F NMR (376 MHz, CDCl 3 )δ -116.96. (s).

[0164] HRMS (ESI): Calcd for C 18 H 17 FONa [M+Na] + : 291.3212; Found 291.3224.

[0165] HPLC conditions: Daicel CHIRALPAK AS-H and AD-H (n-hexane / isopropanol = 99 / 1, 0.5 mL / min, 210 nm); t R (max) = 29.7 min, t R (min) = 35.8 min.

[0166] The above-described embodiments are merely preferred embodiments given to fully illustrate the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are all within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A preparation method of chiral α-alkyl-α-benzyl tetrahydronaphthone compounds, characterized in that, the compound shown in formula I and the compound shown in formula II are reacted in the presence of a palladium catalyst, a chiral ligand, a base reagent and an organic solvent to obtain the chiral α-alkyl-α-benzyl tetrahydronaphthone compound shown in formula III; the structures of the said formula I to formula III are as follows: ， Among them, R 1 is methyl or ethyl; R 2 is hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; the chiral ligand is selected from one or more of the compounds L1 to L12 shown in the following structures: ； the palladium catalyst is selected from one or more of tris(dibenzylideneacetone)dipalladium-chloroform adduct, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene dichloropalladium, allylpalladium(II) chloride dimer, (2,4-cyclopentadien-1-yl)(phenyl-2-propenyl)-palladium, bis(benzonitrile)dichloropalladium, palladium chloride, dichloro(norbornadiene)palladium(II), tris(dibenzylideneacetone)dipalladium, tetraacetonitrile palladium tetrafluoroborate, bis(3,5,3',5'-dimethoxydibenzylideneacetone), palladium trifluoroacetate, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, bis(acetylacetonato)palladium, palladium acetate, bis(dibenzylideneacetone)palladium, palladium iodide, palladium bromide, di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium; the base reagent is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, potassium tert-pentoxide; the solvent is selected from one or more of toluene, benzonitrile, mesitylene, chlorobenzene, o-xylene, p-xylene, n-hexane, cyclohexane, methylcyclohexane, tetrahydrofuran, diethyl ether, 1,4-dioxane, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl ether, n-butyl ether.

2. The preparation method according to claim 1, characterized in that, the molar ratio of the compound shown in formula I to the compound shown in formula II in the feed is 1:2 - 2.

5.

3. The preparation method according to claim 1, characterized in that, the molar ratio of the compound shown in formula I to the palladium catalyst in the feed is 1:0.05 - 1.

4. The preparation method according to claim 1, characterized in that, the molar ratio of the palladium catalyst to the chiral ligand in the feed is 1:2 - 2.

5.

5. The preparation method according to claim 1, characterized in that, the reaction is carried out under an inert atmosphere.

6. The preparation method according to claim 1, characterized in that, the reaction temperature of the reaction is -20 - 100 °C, and the reaction time is not less than 48 h.

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