CN116751118A - Preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compound - Google Patents

Preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compound Download PDF

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CN116751118A
CN116751118A CN202310711676.0A CN202310711676A CN116751118A CN 116751118 A CN116751118 A CN 116751118A CN 202310711676 A CN202310711676 A CN 202310711676A CN 116751118 A CN116751118 A CN 116751118A
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alpha
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张俊良
董宏琳
赵永哲
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Suzhou Kerroli New Material Technology Co ltd
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Abstract

The invention discloses a preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compounds, in particular to an asymmetric benzyl alkylation reaction for preparing high-enantioselectivity and high-yield palladium-catalyzed alpha-alkyl-alpha-benzyl tetralone compounds. The preparation method has the advantages of easily obtained raw materials, wide substrate range, mild reaction conditions, high yield up to 100%, more importantly, good enantioselectivity of the product, and up to 99% ee value, and provides a simple and efficient way for preparing chiral alpha-alkyl-alpha-benzyl tetralone compounds.

Description

Preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compound
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compounds.
Background
Tetrahydronaphthalenone compounds are important intermediates, and have important application in the aspects of medicines, chemical industry, agriculture, new materials, macromolecules and the like, and chiral alpha-alkyl-alpha-benzyl tetrahydronaphthalenone compounds are more commonly existing in natural and non-natural products with biological activity.
The current preparation method for preparing chiral alpha-alkyl tetralone compounds mainly comprises the following steps: chiral tetradentate ligand mediated asymmetric alkylation of achiral lithium enolates (Yamashita, Y.; odashima, K.; koga, K. Tetrahedron letters.1999,40,2803-2806; krein, D.M.; lowry, T.L.In Encyclopedia ofReagents for Organic Synthesis (EROS), 2002,1-4). The transition metal palladium catalyzes the asymmetric allylic alkylation of alpha-alkyltetralone (Trost, B.M.; schroeder, G.M. journal ofthe 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). Wherein, although asymmetric alkylation reaction of chiral tetradentate ligand mediated achiral enol lithium salt can realize asymmetric benzyl, a large amount of transition metal catalyst is needed in the reaction process to react with preformed enol salt; and the transition metal palladium catalyzes the asymmetric allylation of the alpha-alkyl tetralone, and the method cannot be used for preparing the alpha-alkyl-alpha-benzyl tetralone because the alkylating reagent is limited to allylation.
Based on this, a method for synthesizing chiral alpha-alkyl-alpha-benzyl tetralone compounds with high efficiency is needed.
Disclosure of Invention
The invention provides a preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compounds, which takes benzyl alkylating agent, namely trifluoro benzyl acetate with a simple benzene ring as a raw material, and can realize alpha-asymmetric benzyl alkylation of alpha-alkyl tetralone under the catalysis of a palladium catalyst and a specific chiral ligand. The preparation method has the advantages of easily available raw materials, mild reaction conditions, and high product yield and ee value.
In order to solve the technical problems, the invention provides the following technical scheme:
the invention provides a preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compounds, which is characterized in that a compound shown in a formula I reacts with a compound shown in a formula II in the presence of a palladium catalyst, chiral ligand, alkali reagent and organic solvent to obtain chiral alpha-alkyl-alpha-benzyl tetralone compounds shown in a formula III;
the structures of the formulas I to III are as follows:
wherein R is 1 Methyl or ethyl;
R 2 is hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; and R is R 2 1-2 substituent groups can exist on the connected benzene rings, and the substituent groups are the same or different and are respectively selected from one of hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, substituted phenyl, 1-naphthyl and 2-naphthyl;
the chiral ligand has the following structural general formula:
wherein R is C1-C9 alkyl or C7-C9 benzyl;
ar is phenyl or substituted phenyl, wherein the substituent on the substituted phenyl is C1-C4 alkyl;
ad is an adamantyl group, and is a group, t bu is tert-butyl.
Further, adding a palladium catalyst and a chiral ligand into a solvent, stirring for 1-1.5h at 20-30 ℃ to obtain a catalyst solution, and adding an alkali reagent, a compound shown in a formula I and a compound shown in a formula II into the catalyst solution to react to obtain the chiral alpha-alkyl-alpha-benzyl tetralone compound.
Further, the chiral ligand is preferably one or more of the compounds L1 to L12 shown in the following structures:
。
further, the palladium catalyst is preferably one or more of tris (dibenzylideneacetone) dipalladium-chloroform adduct, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthenepalladium dichloride, allylpalladium (II) dichloride, (2, 4-cyclopentadienyl-1-yl) (phenyl-2-propenyl) -palladium, bis (cyanobenzene) palladium dichloride, palladium chloride, dichloro (norbornadiene) palladium (II), tris (dibenzylideneacetone) dipalladium, tetraacetonitrile tetrafluoropalladium borate, bis (3, 5,3',5' -dimethoxydibenzylideneacetone), palladium trifluoroacetate, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride, bis (acetylacetonato) palladium, palladium acetate, bis (dibenzylideneacetone) palladium, palladium iodide, palladium bromide, bis-m-chlorobis [2- [ (dimethylamino) methyl ] phenyl-C, N ] dipalladium; more preferably palladium acetate.
Further, the alkali reagent is preferably one or more of sodium tert-butoxide, potassium tert-butoxide and potassium tert-amyl alcohol; more preferably potassium tert-butoxide.
Further, the solvent is preferably 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, benzotrifluoride, toluene, ethyl acetate, n-hexane, methyl tert-butyl ether, isopropyl ether, n-butyl ether; more preferably benzonitrile.
Further, the molar ratio of the compound of formula I to the compound of formula II 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 molar ratios listed above.
Further, the molar ratio of the compound of formula I to the palladium catalyst 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 molar ratios listed above.
Further, the molar ratio of the compound of formula I to the base agent 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 molar ratios listed above.
Further, the molar ratio of palladium catalyst to chiral ligand 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.
Further, the reaction is carried out under an inert atmosphere, such as nitrogen, argon, and the like, including but not limited to the types of gases listed above.
Further, the reaction temperature of the reaction is-20 to 100 ℃, for example, -20 ℃, -15 ℃, -10 ℃, -5 ℃,0 ℃,5 ℃,10 ℃, 15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃,40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃,70 ℃,75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, etc., including but not limited to the temperature values listed above.
Further, the reaction time of the reaction is not less than 48 hours, more preferably 48 to 72 hours.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compounds, which takes benzyl alkylating agent, namely trifluoro benzyl acetate with simple benzene rings, as a reaction raw material, and can realize alpha-asymmetric benzyl alkylation of alpha-alkyl tetralone under the catalysis of palladium catalyst and specific chiral ligand, the yield of the product prepared by the preparation method is high and can reach 100%, and the ee value can be up to more than 99% by adjusting the reaction temperature.
Detailed Description
Unless defined otherwise, 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 invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The present invention will be further described with reference to specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the present invention and practice it.
Example 1
This example relates to the preparation of chiral ligands L1-L12, each of which has the structure shown below:
taking the preparation of chiral ligand L9 as an example, the specific preparation process is as follows:
(1) A dry 500mL three-necked round bottom bulb was prepared, sodium hydride (185.0 mmol,3.7 equiv.) was added under nitrogen, the rubber stopper was plugged, anhydrous dimethyl sulfoxide (DMSO, 70 mL) was added to the flask via syringe, stirred at 70℃for 2 hours, and the temperature was returned to room temperature. A250 mL single-neck reaction flask was dried, a nitrogen balloon was added to the neck of the flask, xanthene (50.0 mmol,1.0 equiv.) was added under nitrogen, the rubber stopper was plugged, anhydrous DMSO (160 mL) was added to the flask via syringe, stirred until it was completely dissolved, DMSO solution of xanthene was added to the mixture of sodium hydride and DMSO that had been returned to room temperature at room temperature, stirred for 10 minutes, then cyclohexylmethyl bromide (110.0 mmol,2.2 equiv.) was slowly dropped with syringe pump while stirring, at this time touching the flask wall, scalding slightly, and the drop rate of the corresponding bromide was reduced. After the obtained mixture was stirred at room temperature for 1 hour, the reaction system was cooled to 0 ℃ by an ice-water bath, and then the reaction solution was quenched by slowly adding water, extracted 3 times with diethyl ether, separated into a solution, dried over anhydrous magnesium sulfate, and spun-dried. The crude product is dissolved by a solvent (petroleum ether: dichloromethane=2:1), silica gel is filled in an oversized sand core funnel for filtration, the mixture is dried by spin, and the mixture is recrystallized by absolute ethyl alcohol to obtain an intermediate 1, and the structure is as follows:the yield was 77%.
(2) A dry 1000mL three neck round bottom bulb was prepared, intermediate 1 (100.0 mmol,1.0 equiv.) prepared in step (1) was added under nitrogen, the rubber stopper was plugged, and dry methyl tert-butyl ether (100 mL) and dry N, N, N ', N' -tetramethyl ethylenediamine (TMEDA, 75 mL) were added to the flask via syringe, respectively. After stirring at 0℃for 10 minutes, n-BuLi (250.0 mmol,2.5equiv.,2.5M n-BuLi/n-hexane) was added dropwise, and the reaction system was gradually changed from colorless to clear to reddish brown. Then, the reaction mixture was allowed to react at 50℃for 4 hours, the reaction system was further allowed to stand at-50℃and anhydrous tetrahydrofuran (100 mL) was added thereto, followed by stirring for 10 minutes. In addition, a 200mL single-port reaction flask is dried, and I is added 2 Simple substance (250.0 mmol,2.5 equiv.) is added into a flask by a syringe with anhydrous tetrahydrofuran (100 mL) by a rubber stopper, a nitrogen balloon is added into the branch of the flask, and a magnet is rapidly stirred to dissolve I 2 Simple substance, while slowly dripping I 2 To a 1000mL flask, the state of the reaction solution in the flask was observed while avoiding solidification of the reaction solution, which would otherwise affect the yield of the reaction. Then the cooling is turned off, and the mixture is transferred to room temperature and stirred for not less than 4 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate, extracted 3 times with ethyl acetate, separated, and the combined organic phases were dried over anhydrous sodium sulfate and spun-dried. The crude product is dissolved by a solvent (petroleum ether: dichloromethane=2:1), and the intermediate 2 is obtained by beating with methanol, and the structure is as follows:the yield was 73%.
(3) A dry 500mL three-necked round bottom bulb was prepared, 1-adamantane-formaldehyde (82.0 mmol,1.0 equiv.) and t-butylsulfinamide (98.4 mmol,1.2 equiv.) were added under nitrogen atmosphere, a rubber stopper was plugged, anhydrous tetrahydrofuran (200 mL) and tetraisopropyl titanate (123.0 mmol,1.5 equiv.) were added to the flask by syringe, stirring was carried out at 50℃for 4 hours, after the reaction was completed, the reaction system was poured into a 1000mL beaker, saturated saline solution, silica gel was added, stirring was carried out with a glass rod, the reaction solution was filtered with an oversized sand core funnel, washed 4 to 5 times with ethyl acetate, extracted 3 times with ethyl acetate, separated, and the combined anhydrous sodium sulfate solution was addedDrying the organic phase, spin drying, and column chromatography to obtain the productThe yield was 75%.
A dry 250mL three-necked round bottom bulb was prepared, intermediate 2 (30.0 mmol,1.0 equiv.) prepared in step (2) was added under nitrogen atmosphere, a rubber stopper was plugged, anhydrous tetrahydrofuran (70 mL) was added to the flask via syringe, after stirring at 0deg.C for 10 minutes, isopropyl magnesium chloride (33.0 mmol,1.1equiv.,2M isopropyl magnesium chloride/tetrahydrofuran solution) was added dropwise to the reaction system via syringe, stirring at 0deg.C for 2 hours, diphenyl phosphine chloride (30.0 mmol,1.0 equiv.) was added dropwise, and stirring at 0deg.C for 4 hours or more. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted 3 times with ethyl acetate, separated, and the combined organic phases were dried over anhydrous sodium sulfate and spun-dried. Adding 80mL of petroleum ether and 6mL of acetone into the crude product, stirring at normal temperature under the protection of nitrogen for at least 4 hours), and separating out a large amount of white solid, namely intermediate 3The yield was 65%.
(4) A dry 250mL three neck round bottom bulb was prepared, intermediate 3 (19.5 mmol,1.0 equiv.) prepared in step (3) was added under nitrogen, the rubber stopper was plugged, anhydrous dichloromethane (77 mL) was added to the flask via syringe, after stirring at-78deg.C for 10 min, n-BuLi (21.5 mmol,1.1equiv.,2.5M n-BuLi/n-hexane solution) was added dropwise, and stirring was performed at-78deg.C for 1 h. In addition, a 50mL single-mouth reaction bottle is dried, a nitrogen balloon is added into the branch mouth of the flask, and the mixture is added under the nitrogen atmosphere(23.4 mmol,1.2 equiv.) a rubber stopper was plugged, anhydrous dichloromethane (20 mL) was added to the flask via syringe, after stirring at-78℃for 10 min, boron trifluoride etherate (25.4 mmol,1.3 equiv.) was added dropwise, the mixture was slowly added via syringe along the inner wall to a 250mL three-necked round bottom bulb, and cooled and stirred overnight. ReactionAfter completion, the reaction solution was quenched with saturated aqueous ammonium chloride, extracted 3 times with ethyl acetate, separated, and the combined organic phases were dried over anhydrous sodium sulfate and spun dry. Column chromatography (petroleum ether: ethyl acetate=5:1) gives the product chiral ligand L9. And carrying out nuclear magnetism and mass spectrum characterization on the product, wherein the characterization result is as follows:
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).
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.
31 PNMR(162MHz,CDCl 3 )δ-17.16.
HRMS(ESI):calculated for[C 54 H 68 NO 2 PS][M+H] + :826.1620,found826.1637.
the preparation of chiral ligands L1-L8 and L10-L12 is the same as the preparation method of chiral ligand L9.
Example 2
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3aa, having the structure shown below:
the preparation process comprises the following steps:
a dry 10mL vial was taken, a magnet of the appropriate size was placed, the palladium catalyst (0.005 mmol,5 mol%) and chiral ligand (0.01 mmol,10 mol%) were accurately weighed and added to the vial, and the stopper was screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted solvent (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. Then the vial was introduced into a glove box, an alkali reagent (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and α -methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and benzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial by a microinjector, and the vial stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was measured by GC and the ee value was determined by HPLC.
(1) Influence of different palladium catalysts on the reaction yield and ee value
In the preparation process, the chiral ligand is L1, the solvent is toluene, the alkali reagent is sodium tert-butoxide, the reaction is stirred at 75 ℃ for 48 hours, the influence of different palladium catalysts on the reaction yield and ee is studied, and the results are shown in Table 1:
TABLE 1
As can be seen from Table 1, the reaction rate was relatively fast and the ee value of the produced product was highest when the palladium catalyst was palladium acetate under the same other conditions.
(2) Influence of different solvents on the reaction yield and ee value
In the preparation process, palladium catalyst is palladium acetate, chiral ligand is L1, alkali reagent is sodium tert-butoxide, reaction is stirred for 48 hours at 75 ℃, influence of different solvents on reaction yield and ee is studied, and the result is shown in Table 2:
TABLE 2
As is clear from Table 2, the ee value of the product was highest when the solvent was benzonitrile under the same conditions.
(3) Influence of different alkaline reagents on the reaction yield and ee value
In the preparation process, palladium catalyst is palladium acetate, chiral ligand is L1, solvent is benzonitrile, the reaction is stirred for 48 hours at 75 ℃, the influence of different alkali reagents on reaction yield and ee is studied, and the results are shown in Table 3:
TABLE 3 Table 3
Potassium tert-butoxide a : reacting at 25 ℃ for 48 hours; potassium tert-butoxide b : the reaction was carried out at 0℃for 48 hours.
As can be seen from Table 3, under the same conditions, when the alkali agent is potassium t-butoxide, the reaction is carried out at 0℃for 48 hours with stirring, the yield of the product can be as high as 98%, and the ee value of the product can be as high as 85%.
(4) Influence of different chiral ligands on reaction yield, ee
In the preparation process, palladium catalyst is palladium acetate, solvent is benzonitrile, alkali reagent is potassium tert-butoxide, the reaction is stirred for 48 hours at 0 ℃, the influence of different chiral ligands on reaction yield and ee is studied, and the results are shown in Table 4:
TABLE 4 Table 4
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As can be seen from Table 4, under the other conditions, when the chiral ligand is any one of the compounds L1 to L3, the product yield can be as high as 100% by stirring the mixture at 0℃for 48 hours, wherein the ee value of the product prepared by using the chiral ligand L1 as a chiral catalyst can be as high as 85%. When any one of the chiral ligand L6-L12 is used as a chiral catalyst, the ee value of the obtained product is not lower than 88%. When the analogue D1 is used as a chiral catalyst, the reaction system only obtains a very small amount of chiral alpha-alkyl-alpha-benzyl tetralone 3aa after stirring for 48 hours.
The product obtained by the preparation is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝6.4Hz,1H),7.43(t,J＝6.7Hz,1H),7.32-7.27(m,1H),7.25(d,J＝6.8Hz,2H),7.17(dd,J＝19.0,6.8Hz,4H),3.09(d,J＝13.4Hz,1H),2.97(t,J＝5.9Hz,2H),2.84(d,J＝13.4Hz,1H),2.03-1.94(m,1H),1.83(m,J＝13.7,5.8Hz,1H),1.16(s,3H).
13 C NMR(101MHz,CDCl 3 )δ201.99,143.23,137.69,133.15,131.80,130.75,128.70,128.12,127.98,126.72,126.33,45.84,42.74,33.07,25.48,22.38.
HRMS(ESI):Calcd for C 18 H 18 ONa[M+Na] + :273.3307；Found 273.3394。
HPLC conditions: daicel CHIRALPAKAS-H and AD-H (n-hexane/isopropanol=99/1, 0.5ml/min,210 nm); t is t R (max) =30.8 min, t R (minimum) =35.3 min.
Example 3
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ab, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 4-phenylbenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 89% by GC and the ee value was greater than 99% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,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).
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.
HRMS(ESI):Calcd for C 24 H 22 ONa[M+Na] + :349.4285；Found 349.4278.
HPLC conditions: daicel CHIRALPAKAS-H and AD-H (n-hexane/isopropanol=99/1, 0.5ml/min,210 nm); t is t R (max) =40.6 min, t R (minimum) =46.3 min.
Example 4
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ac, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 4-methylbenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 89% by GC and the ee value was greater than 99% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝7.9Hz,1H),7.43(m,J＝7.4,1.5Hz,1H),7.31-7.26(m,1H),7.19(d,J＝7.6Hz,1H),7.07-7.01(m,4H),3.05(d,J＝13.5Hz,1H),2.96(q,J＝5.6Hz,2H),2.80(d,J＝13.5Hz,1H),2.29(s,3H),1.98(m,J＝13.7,8.1,5.7Hz,1H),1.85-1.79(m,1H),1.15(s,3H).
13 C NMR(101MHz,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.
HRMS(ESI):Calcd for C 19 H 20 ONa[M+Na] + :287.3576；Found 287.3583.
HPLC conditions: daicel CHIRALPAKAS-H and AD-H (n-hexane/isopropanol=99/1, 0.5ml/min,210 nm); t is t R (max) =28.4 min, t R (minimum) =31.2 min.
Example 5
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ad, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 3-methoxybenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 91% by GC and the ee value 86% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl3)δ8.12(d,J＝9.3Hz,1H),7.48(m,J＝7.5,1.5Hz,1H),7.34(t,J＝7.0Hz,1H),7.25-7.18(m,2H),6.80-6.74(m,3H),3.80(s,3H),3.14(d,J＝13.3Hz,1H),3.01(t,J＝6.4Hz,2H),2.86(d,J＝13.4Hz,1H),2.04(m,J＝13.9,6.9Hz,1H),1.88(m,J＝13.7,5.7Hz,1H),1.22(s,3H).
13 C NMR(101MHz,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.
HRMS(ESI):Calcd for C 19 H 20 O 2 Na[M+Na] + :303.3576；Found 303.3589.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (n-hexane/isopropanol=99/1, 0.5mL/min,210 nm); t is t R (max) =43.1 min, t R (minimum) =46.9 min.
Example 6
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ae, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 2-methylbenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 94% by GC and the ee value 86% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝6.4Hz,1H),7.43(m,J＝7.4,1.5Hz,1H),7.32-7.27(m,1H),7.19(d,J＝7.6Hz,1H),7.13-7.10(m,1H),7.09-7.05(m,3H),3.07(d,J＝3.0Hz,2H),2.96(t,J＝6.4Hz,2H),2.30(s,3H),2.07(m,J＝14.0,7.1Hz,1H),1.90(m,J＝13.6,5.6Hz,1H),1.17(s,3H).
13 C NMR(101MHz,CDCl3)δ137.35,136.34,133.15,131.89,131.30,130.51,128.69,128.17,126.75,126.34,125.50,46.74,38.57,33.53,25.43,22.30,20.59.
HRMS(ESI):C 19 H 20 ONa[M+Na] + :287.3576；Found 287.3564.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (n-hexane/isopropanol=99/1, 0.5mL/min,210 nm); t is t R (max) =25.1 min, t R (minimum) =38.6 min.
Example 7
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3af having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 2-chlorobenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 53% by GC and the ee value 80% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝6.4Hz,1H),7.48(m,J＝7.4,1.5Hz,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＝14.4,9.0,5.7Hz,1H),2.02(m,J＝13.7,5.4Hz,1H),1.26(s,3H).
13 C NMR(101MHz,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.
HRMS(ESI):Calcd for C 18 H 17 ClONa[M+Na] + :307.7728；Found 307.7735.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (n-hexane/isopropanol=99/1, 0.5mL/min,210 nm); t is t R (max) =24.9 min, t R (minimum) =32.7 min.
Example 8
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ag, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 1-naphthyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial by a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 91% by GC and the ee value 80% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝6.4Hz,1H),7.48(m,J＝7.4,1.5Hz,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＝14.4,9.0,5.7Hz,1H),2.02(m,J＝13.7,5.4Hz,1H),1.26(s,3H).
13 C NMR(101MHz,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.
HRMS(ESI):Calcd for C 18 H 17 ClONa[M+Na] + :307.7728；Found 307.7735.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (n-hexane/isopropanol=99/1, 0.5mL/min,210 nm); t is t R (max) =45.3 min, t R (minimum) =56.3 min.
Example 9
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ah, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 3-methylbenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 98% by GC and the ee value was 88% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝6.4Hz,1H),7.50(m,J＝7.4,1.5Hz,1H),7.38-7.33(m,1H),7.26(d,J＝7.7Hz,1H),7.20(t,J＝7.5Hz,1H),7.04(dd,J＝21.8,9.1Hz,3H),3.12(d,J＝13.4Hz,1H),3.06-2.99(m,2H),2.87(d,J＝13.4Hz,1H),2.37(s,3H),2.05(m,J＝13.8,8.0,5.9Hz,1H),1.89(m,J＝13.7,5.6Hz,1H),1.22(s,3H).
13 C NMR(101MHz,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.
HRMS(ESI):Calcd for C 19 H 20 ONa[M+Na] + :287.3576；Found 287.3569.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (Positive)Hexane/isopropanol=99/1, 0.5ml/min,210 nm); t is t R (max) =23.6 min, t R (minimum) =26.6 min.
Example 10
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ai, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 3-fluorobenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 90% by GC and the ee value was 89% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝7.9Hz,1H),7.45(t,J＝7.4Hz,1H),7.33-7.28(m,1H),7.19(dd,J＝10.0,7.7Hz,2H),6.89(dd,J＝21.1,8.1Hz,3H),3.13(d,J＝13.4Hz,1H),3.01-2.94(m,2H),2.82(d,J＝13.4Hz,1H),1.99(m,J＝14.2,8.5,5.9Hz,1H),1.84(m,J＝13.7,5.5Hz,1H),1.17(s,3H).
13 C NMR(101MHz,CDCl 3 )δ201.57,163.75,161.32,143.10,131.66,129.34,129.26,128.70,128.14,126.77,126.44,126.41,117.59,117.39,113.33,113.12,45.83,42.65,33.07,25.40,22.38.
19 F NMR(376MHz,CDCl3)δ-113.92(s).
HRMS(ESI):Calcd for C 18 H 17 FONa[M+Na] + :291.3212；Found 291.3201.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (n-hexane/isopropanol=99/1, 0.5mL/min,210 nm); t is t R (max) =26.8 min, t R (minimum) =30.7 min.
Example 11
This example relates to the preparation of chiral α -alkyl- α -benzyltetralone 3ai, having the structure shown below:
the preparation process is as follows:
a dried 10mL vial was taken, placed in a magnet of appropriate size, accurately weighed palladium acetate (0.005 mmol,5 mol%), chiral ligand L9 (0.01 mmol,10 mol%) and added to the vial, and the stopper screwed (without screwing). And then, under the protection of nitrogen, performing air pumping and air exchanging operation for 3-4 times, so that the whole sealing tube is in the nitrogen atmosphere. The stopper was opened by introducing nitrogen, and the extracted benzonitrile (1.0 mL) was added to the vial with a syringe, and the stopper was screwed. The stirring speed was adjusted and stirred at room temperature for 1 hour. The vial was then placed in a glove box, potassium tert-butoxide (0.35 mmol,3.5 equiv.) was accurately weighed into the vial, and alpha-methyltetrahydronaphthalenone (0.1 mmol,1.0 equiv.) and 4-fluorobenzyl trifluoroacetate (0.3 mmol,2.0 equiv.) were accurately measured into the vial with a microinjector, and the stopper was screwed. And (5) adjusting the stirring speed, and carrying out stirring reaction. Filtering after the reaction is finished, spinning the obtained filtrate into dichloromethane and ethyl acetate by using a rotary evaporator, transferring the residual liquid into a bottle as small as possible, plugging cotton by a tap, uniformly heating the bottle body by using a blower, pumping for about 10 minutes by using an oil pump until the solvent is completely pumped out, and separating by using column chromatography (n-hexane: ethyl acetate=1000:1) to obtain the product. The yield was 92% by GC and the ee value 78% by HPLC.
The prepared product is subjected to 1 H NMR、 13 C NMR, HRMS and HPLC characterization, the characterization results are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.10(d,J＝7.9Hz,1H),7.48(t,J＝8.2Hz,1H),7.34(t,J＝7.5Hz,1H),7.24(d,J＝7.7Hz,1H),6.96(t,J＝8.7Hz,2H),3.13(d,J＝13.6Hz,1H),3.01(t,J＝6.4Hz,2H),2.84(d,J＝13.6Hz,1H),2.02(m,J＝14.0,7.0Hz,1H),1.87(m,J＝13.6,5.7Hz,1H),1.19(s,3H).
13 C NMR(101MHz,CDCl 3 )δ201.75,162.89,160.46,143.13,133.36,133.33,133.21,132.08,132.01,131.72,128.70,128.08,126.75,114.86,114.65,42.03,33.06,22.37.
19 F NMR(376MHz,CDCl 3 )δ-116.96.(s).
HRMS(ESI):Calcd for C 18 H 17 FONa[M+Na] + :291.3212；Found 291.3224.
HPLC conditions: daicel CHIRALPAK AS-H and AD-H (n-hexane/isopropanol=99/1, 0.5mL/min,210 nm); t is t R (max) =29.7 min, t R (minimum) =35.8 min.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.

Claims (10)

1. The preparation method of the chiral alpha-alkyl-alpha-benzyl tetralone compound is characterized in that a compound shown in a formula I and a compound shown in a formula II are reacted in the presence of a palladium catalyst, a chiral ligand, an alkali reagent and an organic solvent to obtain the chiral alpha-alkyl-alpha-benzyl tetralone compound shown in a formula III;
the structures of the formulas I to III are as follows:
wherein R is 1 Methyl or ethyl;
R 2 is hydrogen, halogen, alkyl, alkoxy, trifluoromethyl, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl;
the chiral ligand has the following structural general formula:
wherein R is C1-C9 alkyl or C7-C9 benzyl;
ar is phenyl or substituted phenyl, wherein the substituent on the substituted phenyl is C1-C4 alkyl;
ad is an adamantyl group, and is a group, t bu is tert-butyl.
2. The preparation method according to claim 1, wherein the chiral ligand is selected from one or more of the compounds L1 to L12 represented by the following structures:
3. the process according to claim 1, wherein the palladium catalyst is selected from one or more of tris (dibenzylideneacetone) dipalladium-chloroform adduct, 4, 5-bis (diphenylphosphine-9, 9-dimethylxanthenepalladium dichloride, allylpalladium (II) chloride dimer, (2, 4-cyclopentadien-1-yl) (phenyl-2-propenyl) -palladium, bis (cyanobenzenepalladium dichloride, palladium chloride, dichloro (norbornadiene) palladium (II), tris (dibenzylideneacetone) dipalladium, tetraacetonitrile tetrafluoropalladium, bis (3, 5,3',5' -dimethoxydibenzylideneacetone), palladium trifluoroacetate, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride, bis (acetylacetonate) palladium, palladium acetate, bis (dibenzylideneacetone) palladium, palladium iodide, palladium bromide, bis- μm-chloro bis [2- [ (dimethylamino) methyl ] phenyl-C, N ] dipalladium.
4. The preparation method according to claim 1, wherein the alkaline reagent is one or more selected from sodium tert-butoxide, potassium tert-butoxide and potassium tert-amyl alcohol.
5. The method according to claim 1, wherein the solvent is one or more selected from toluene, benzonitrile, mesitylene, chlorobenzene, o-xylene, p-xylene, n-hexane, cyclohexane, methylcyclohexane, tetrahydrofuran, diethyl ether, 1, 4-dioxane, cyclopentylmethyl ether, benzotrifluoride, toluene, ethyl acetate, n-hexane, methyl t-butyl ether, isopropyl ether, and n-butyl ether.
6. The method of claim 1, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:2-2.5.
7. The method of claim 1, wherein the molar ratio of the compound of formula I to the palladium catalyst is 1:0.05-1.
8. The method of claim 1, wherein the molar ratio of palladium catalyst to chiral ligand is 1:2-2.5.
9. The method of claim 1, wherein the reaction is carried out under an inert atmosphere.
10. The method according to claim 1, wherein the reaction temperature of the reaction is-20 to 100 ℃ and the reaction time is not less than 48 hours.
CN202310711676.0A 2023-06-15 2023-06-15 Preparation method of chiral alpha-alkyl-alpha-benzyl tetralone compound Pending CN116751118A (en)

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