CN113387771A - Preparation method of chiral fluoroalkyl ternary carbocyclic compound - Google Patents

Preparation method of chiral fluoroalkyl ternary carbocyclic compound Download PDF

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CN113387771A
CN113387771A CN202110664957.6A CN202110664957A CN113387771A CN 113387771 A CN113387771 A CN 113387771A CN 202110664957 A CN202110664957 A CN 202110664957A CN 113387771 A CN113387771 A CN 113387771A
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毕锡和
张欣宇
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Northeastern University China
Northeast Normal University
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    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
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    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract

The invention provides a preparation method of a chiral fluoroalkyl ternary carbocyclic compound, and belongs to the technical field of organic synthesis. According to the method, fluoroalkyl sulfonyl hydrazone derivatives are used as raw materials, and are decomposed in situ under an alkaline condition, so that fluoroalkyl diazo compounds are generated in situ, and the generated fluoroalkyl diazo compounds are subjected to asymmetric [2+1] cycloaddition reaction with alkyne derivatives or alkene derivatives respectively to realize conversion of the fluoroalkyl diazo compounds, so that chiral fluoroalkyl cyclopropene and chiral fluoroalkyl cyclopropane with optical activity are synthesized.

Description

Preparation method of chiral fluoroalkyl ternary carbocyclic compound
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a chiral fluoroalkyl ternary carbocyclic compound.
Background
Chiral fluoroalkyl-substituted three-membered carbocyclic compounds are often found in a variety of pharmaceutical candidate compounds and agricultural organic molecules as an important class of organic structural units. Their unique spatial structure, electronic properties, and optical activity also make them frequently used as functional group substitutes in the core structures of a variety of analgesics, pesticides, and antibiotics to improve their biological activity. Meanwhile, the existence of high strain tension also enables the compound to become a chiral synthon with high activity and to be widely applied to organic synthesis.
The [2+1] asymmetric cycloaddition reaction of fluoroalkyl carbene, alkyne and alkene is the most convenient and direct method for synthesizing fluoroalkyl ternary carbocyclic compound with optical activity. However, the existing synthesis process needs to prepare the corresponding fluoroalkyl diazomethane solution or gas in advance, and then slowly add the solution or gas into the reaction system through a syringe pump or nitrogen blowing. However, fluoroalkyl diazomethanes have high volatility, high toxicity and high explosiveness, which greatly limit their preparation, purification, storage and use. Therefore, the existing method for preparing chiral fluoroalkyl cyclopropene and fluoroalkyl cyclopropane has great potential safety hazard and is not suitable for large-scale industrial application.
Disclosure of Invention
The invention aims to provide a preparation method of a chiral fluoroalkyl ternary carbocyclic compound, which is safe, mild, efficient and suitable for industrial application.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of a chiral fluoroalkyl ternary carbocyclic compound, which comprises the following steps:
when the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropene compound:
mixing fluoroalkyl sulfonyl hydrazone derivatives with a structure shown in a formula I, alkyne derivatives with a structure shown in a formula II, a first chiral metal catalyst, a first alkali compound and a first organic solvent, and carrying out a first [2+1] cycloaddition reaction to obtain chiral fluoroalkyl cyclopropene compounds with a structure shown in a formula III;
when the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropane compound:
mixing fluoroalkyl sulfonyl hydrazone derivatives with a structure shown in a formula I, olefin derivatives with a structure shown in a formula IV, a second chiral metal catalyst, a second base compound and a second organic solvent, and performing a second [2+1] cycloaddition reaction to obtain chiral fluoroalkyl cyclopropane compounds with a structure shown in a formula V;
Figure BDA0003116946390000021
in the formulae I to V, R is1、R2、R3、R4、R5And R6Independently of each other is H, alkyl, C3～C27Cycloalkyl radical, C3～C9Heterocyclic group, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10Heteroaryl, substituted alkyl, substituted C3～C27Cycloalkyl, substituted C3～C9Heterocyclyl, substituted C2～C29Alkenyl, substituted C2～C29Alkynyl, substituted C6～C10Aryl or substituted C5～C10A heteroaryl group; the substituted substituent is independently halogen, nitryl, cyano, ester group, C1～C8Alkyl radical, C1～C8Fluoroalkyl radical, C1～C4Alkoxy or C6～C10An aryl group;
the R isfIndependently is HCF2-、H2CF-、CF3-or has CnF2n+1Fluoroalkyl with a general structural formula, wherein n is 1-15.
Preferably, said R is1Is phenyl or biphenyl; the R is2Is fluoromethylphenyl; the R is3Is hydrogen, phenyl, cyclopentyl or methoxyphenyl; the R is4Is hydrogen; the R is5Is phenyl or hydrogen; the R is6Is hydrogen.
Preferably, the molar ratio of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I to the alkyne derivative with the structure shown in the formula II is (1-5): 1; the molar ratio of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I to the olefin derivative with the structure shown in the formula IV is (1-5): 1.
Preferably, the first chiral metal catalyst and the second chiral metal catalyst are independently
Figure BDA0003116946390000031
Wherein, X1、X2、X3、X4、X5、X6And X7Independently H, halogen, nitro, cyano, ester group, C1～C27Alkyl radical, C1～C9Fluoroalkyl radical, C1～C4Alkoxy radical, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10A heteroaryl group containing N, O or S.
Preferably, the molar ratio of the first chiral metal catalyst to the second chiral metal catalyst to the trifluoromethylsulfonyl hydrazone derivative with the structure shown in the formula I is independently (0.0001-0.2): 1.
Preferably, the first base compound and the second base compound are independently one or more of 1, 8-diazohetero-spiro [5.4.0] undec-7-ene, 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, 157-triazabicyclo (4.4.0) dec-5-ene, tetramethylguanidine, triethylamine, tri-tert-butylamine, triethylenediamine, 4-dimethylaminopyridine, N-diisopropylethylamine, pyridine, sodium hydride, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate and potassium phosphate.
Preferably, the molar ratio of the first base compound to the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I is (1-5): 1.
Preferably, the molar ratio of the second base compound to the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I is (1-5): 1.
Preferably, the reaction temperature of the first [2+1] cycloaddition reaction and the reaction temperature of the second [2+1] cycloaddition reaction are independently-78-60 ℃, and the reaction time is independently 2-48 h.
Preferably, the first organic solvent and the second organic solvent are independently one or more of toluene, acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethyl acetate and water.
The invention provides a preparation method of a chiral fluoroalkyl ternary carbocyclic compound, which takes fluoroalkyl sulfonyl hydrazone derivatives as raw materials, and under the alkaline condition, the fluoroalkyl sulfonyl hydrazone derivatives are decomposed in situ to generate fluoroalkyl diazo compounds in situ, and the generated fluoroalkyl diazo compounds are subjected to asymmetric [2+1] cycloaddition reaction with alkyne derivatives or alkene derivatives respectively to realize conversion of the fluoroalkyl diazo compounds, so as to synthesize chiral fluoroalkyl cyclopropene and chiral fluoroalkyl cyclopropane with optical activity.
The method takes cheap and easily-obtained fluoroalkyl sulfonyl hydrazone derivatives and alkyne derivatives or olefin derivatives as raw materials, and asymmetric [2+1] cycloaddition reaction is carried out under the catalysis of chiral metal catalysts, so that fluoroalkyl-substituted cyclopropane and fluoroalkyl-substituted cyclopropane derivatives with important biological activity can be efficiently synthesized with high enantioselectivity.
Drawings
FIG. 1 is a drawing of Compound 3a prepared in example 11H nuclear magnetic resonance spectrogram;
FIG. 2 is a photograph of Compound 3a prepared in example 113C nuclear magnetic resonance spectrogram;
FIG. 3 is a photograph of Compound 3a prepared in example 119F nuclear magnetic resonance spectrogram;
FIG. 4 is a photograph of Compound 3b prepared in example 21H nuclear magnetic resonance spectrogram;
FIG. 5 is a photograph of Compound 3b prepared in example 213C nuclear magnetic resonance spectrogram;
FIG. 6 is a drawing of Compound 3b prepared in example 219F nuclear magnetic resonance spectrogram;
FIG. 7 is a photograph of Compound 3c prepared in example 31H nuclear magnetic resonance spectrogram;
FIG. 8 is a photograph of Compound 3c prepared in example 313C nuclear magnetic resonance spectrogram;
FIG. 9 is a photograph of Compound 3c prepared in example 319F nuclear magnetic resonance spectrogram;
FIG. 10 is of Compound 3d, prepared in example 41H nuclear magnetic resonance spectrogram;
FIG. 11 is a photograph of Compound 3d prepared in example 413C nuclear magnetic resonance spectrogram;
FIG. 12 is of Compound 3d, prepared in example 419F nuclear magnetic resonance spectrogram;
FIG. 13 is a photograph of Compound 3e prepared in example 51H nuclear magnetic resonance spectrogram;
FIG. 14 is a photograph of Compound 3e prepared in example 513C nuclear magnetic resonance spectrogram;
FIG. 15 is a photograph of Compound 3e prepared in example 519F nuclear magnetic resonance spectrum.
Detailed Description
The invention provides a preparation method of a chiral fluoroalkyl ternary carbocyclic compound, which comprises the following steps:
when the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropene compound:
mixing fluoroalkyl sulfonyl hydrazone derivatives with a structure shown in a formula I, alkyne derivatives with a structure shown in a formula II, a first chiral metal catalyst, a first alkali compound and a first organic solvent, and carrying out a first [2+1] cycloaddition reaction to obtain chiral fluoroalkyl cyclopropene compounds with a structure shown in a formula III;
when the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropane compound:
mixing fluoroalkyl sulfonyl hydrazone derivatives with a structure shown in a formula I, olefin derivatives with a structure shown in a formula IV, a second chiral metal catalyst, a second base compound and a second organic solvent, and performing a second [2+1] cycloaddition reaction to obtain chiral fluoroalkyl cyclopropane compounds with a structure shown in a formula V;
Figure BDA0003116946390000051
in the formulae I to V, R is1、R2、R3、R4、R5And R6Independently of each other is H, alkyl, C3～C27Cycloalkyl radical, C3～C9Heterocyclic group, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10Heteroaryl, substituted alkyl, substituted C3～C27Cycloalkyl, substituted C3～C9Heterocyclyl, substituted C2～C29Alkenyl, substituted C2～C29Alkynyl, substituted C6～C10Aryl or substituted C5～C10A heteroaryl group; the substituted substituent is independently halogen, nitryl, cyano, ester group, C1～C8Alkyl radical, C1～C8Fluoroalkyl radical, C1～C4Alkoxy or C6～C10An aryl group;
the R isfIndependently is HCF2-、H2CF-、CF3-or has CnF2n+1Fluoroalkyl with a general structural formula, wherein n is 1-15.
In the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.
When the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropene compound, the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I, the alkyne derivative with the structure shown in the formula II, a first chiral metal catalyst, a first alkali compound and a first organic solvent are mixed to perform a first [2+1] cycloaddition reaction, so that the chiral fluoroalkyl cyclopropene compound with the structure shown in the formula III is obtained.
In the invention, the structural formula of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I is shown in the specification
Figure BDA0003116946390000061
In the formula I, R is1、R2、R3And R4Independently of each other is H, alkyl, C3～C27Cycloalkyl radical, C3～C9Heterocyclic group, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10Heteroaryl, substituted alkyl, substituted C3～C27Cycloalkyl, substituted C3～C9Heterocyclyl, substituted C2～C29Alkenyl, substituted C2～C29Alkynyl, substituted C6～C10Aryl or substituted C5～C10A heteroaryl group; the substituted substituent is independently halogen, nitryl, cyano, ester group, C1～C8Alkyl radical, C1～C8Fluoroalkyl radical, C1～C4Alkoxy or C6～C10An aryl group; the R isfIs HCF2-、H2CF-、CF3-or has CnF2n+1Fluoroalkyl with a general structural formula, wherein n is 1-15.
In the present invention, the preparation process of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in formula I preferably includes: dissolving a substituted sulfonyl hydrazide compound a (30mmol) and a substituted ketone compound b (30mmol) in 40mL of Ethyl Acetate (EA) under the condition of nitrogen, adding boron trifluoride diethyl etherate (45mmol), reacting the obtained material in an oil bath kettle at 40 ℃ overnight, adding 40mL of saturated sodium chloride aqueous solution (mass concentration is 1.33g/mL) into the obtained product after the reaction is finished, extracting with EA, drying the obtained extract with magnesium sulfate, concentrating under reduced pressure, and carrying out silica gel column chromatography on the obtained product to obtain the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I, wherein the specific process is shown as the following formula A:
Figure BDA0003116946390000062
in the formula A, R is1、R2And RfThe same as in the structure of formula I above, and will not be described herein again.
The process of EA extraction, drying with magnesium sulfate, concentration under reduced pressure, and silica gel column chromatography separation in the present invention is not particularly limited, and may be performed according to a process well known in the art.
In the present invention, said R1Preferably phenyl or biphenyl; the R is2Preferably fluoromethylphenyl; the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I is preferably a fluoroalkyl sulfonyl hydrazone derivative
Figure BDA0003116946390000071
Figure BDA0003116946390000072
In the invention, the alkyne derivative with the structure shown in the formula II has the structural formula
Figure BDA0003116946390000073
The alkyne derivative having the structure shown in formula II is not particularly limited in the present invention, and can be prepared by commercially available methods or methods well known in the art.
In the present invention, said R3Preferably hydrogen, phenyl, cyclopentyl or methoxyphenyl; the R is4Preferably hydrogen; the alkyne derivative with the structure shown in the formula II is preferably
Figure BDA0003116946390000074
Figure BDA0003116946390000075
In the invention, the molar ratio of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I to the alkyne derivative with the structure shown in the formula II is preferably 1 (1-5), and more preferably 1 (2-3).
In the present invention, the first chiral metal catalyst is preferably:
Figure BDA0003116946390000081
wherein, X1、X2、X3、X4、X5、X6And X7Independently preferably H, halogen, nitro, cyano, ester group, C1～C27Alkyl radical, C1～C9Fluoroalkyl radical, C1～C4Alkoxy radical, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10A heteroaryl group containing N, O or S.
In the present invention, the first chiral metal catalyst preferably has a structural formula
Figure BDA0003116946390000082
Is recorded as Rh2(R-BTPCP)4；
Alternatively, the first chiral metal catalyst preferably has a structural formula
Figure BDA0003116946390000083
Is recorded as Rh2(R-PTAD)4。
In the present invention, the chiral catalyst is preferably commercially available or prepared according to the method disclosed in the patent (CN110483272A, published 2019, 11 and 22).
In the present invention, the molar ratio of the first chiral metal catalyst to the trifluoromethylsulfonyl hydrazone derivative having the structure represented by formula I is preferably (0.0001-0.2): 1, more preferably (0.0005-0.15): 1, and still more preferably (0.005-0.1): 1.
In the present invention, the first base compound is preferably one or more of 1, 8-diazoheterobis [5.4.0] undec-7-ene (DBU), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD), 1,5, 7-triazabicyclo (4.4.0) dec-5-ene (TBD), Tetramethylguanidine (TMG), triethylamine (Et3N), tri-tert-butylamine (Bu3N), triethylenediamine (DABCO), 4-Dimethylaminopyridine (DMAP), N-Diisopropylethylamine (DIPEA), pyridine, sodium hydride, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate and potassium phosphate; when the first alkali compound is a plurality of the above, the proportion of different alkali compounds is not particularly limited, and any proportion can be adopted.
In the invention, the molar ratio of the first base compound to the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I is preferably (1-5): 1, and more preferably (2-3): 1.
In the invention, the first organic solvent is preferably one or more of toluene, acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethyl acetate and water; when the first organic solvent is one of the above, the invention has no special limitation on the mixture ratio of different organic solvents, and any mixture ratio can be used.
In the invention, the first organic solvent is preferably used in an amount such that the concentration of the fluoroalkyl sulfonyl hydrazone derivative having the structure represented by formula I is 0.1-3 mmol/mL.
The process of mixing the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I, the alkyne derivative with the structure shown in the formula II, the first chiral metal catalyst, the first alkali compound and the first organic solvent is not particularly limited, and the materials can be uniformly mixed according to the process known in the art.
In the invention, the first [2+1] cycloaddition reaction is preferably carried out under the conditions of nitrogen and stirring, the reaction temperature of the first [2+1] cycloaddition reaction is preferably-78-60 ℃, and the reaction time is preferably 2-48 h, more preferably 12-36 h, and further preferably 24 h. The stirring process is not particularly limited in the present invention, and the reaction can be carried out smoothly according to the process known in the art.
In the present invention, the process of the first [2+1] cycloaddition reaction is represented by the following formula:
Figure BDA0003116946390000091
after the first [2+1] cycloaddition reaction is completed, the invention preferably filters the obtained product by diatomite, concentrates the obtained filtrate under reduced pressure, and then carries out silica gel column chromatography separation to obtain the chiral fluoroalkyl cyclopropene compound with the structure shown in formula III. The processes of filtering, concentrating under reduced pressure and separating by silica gel column chromatography are not particularly limited, and can be carried out according to the processes well known in the art.
In the invention, the chiral fluoroalkyl cyclopropene compound with the structure shown in formula III is preferably
Figure BDA0003116946390000101
In the invention, when the chiral fluoroalkyl ternary carbocycle compound is a chiral fluoroalkyl cyclopropane compound, the alkyne derivative with the structure shown in the formula II is replaced by the alkene derivative with the structure shown in the formula IV, and other processes are the same as the process for preparing the chiral fluoroalkyl cyclopropene compound with the structure shown in the formula III.
In the invention, the structural formula of the olefin derivative with the structure shown in the formula IV is shown in the specification
Figure BDA0003116946390000102
The R is3、R4、R5And R6Independently of each other is H, alkyl, C3～C27Cycloalkyl radical, C3～C9Heterocyclic group, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10Heteroaryl, substituted alkyl, substituted C3～C27Cycloalkyl, substituted C3～C9Heterocyclyl, substituted C2～C29Alkenyl, substituted C2～C29Alkynyl, substituted C6～C10Aryl or substituted C5～C10A heteroaryl group; the substituted substituent is independently halogen, nitryl, cyano, ester group, C1～C8Alkyl radical, C1～C8Fluoroalkyl radical, C1～C4Alkoxy or C6～C10And (4) an aryl group. The present invention is not particularly limited with respect to the source of the olefin derivative having the structure represented by formula IV, and any of the olefin derivatives can be prepared by commercially available methods well known in the art or by well-known methods.
In the present invention, said R5Preferably phenyl or hydrogen; the R is6Preferably hydrogen; the olefin derivative with the structure shown in the formula IV is preferably
Figure BDA0003116946390000103
In the invention, the molar ratio of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I to the olefin derivative with the structure shown in the formula IV is preferably (1-5): 1, and more preferably (2-3): 1.
In the present invention, the second chiral metal catalyst is preferably the same as the first chiral metal catalyst, and will not be described herein. In the present invention, the molar ratio of the second chiral metal catalyst to the trifluoromethylsulfonylhydrazone derivative having a structure represented by formula I is preferably (0.0001 to 0.2):1, more preferably (0.0005 to 0.15):1, and still more preferably (0.005 to 0.1): 1.
In the present invention, the second base compound is preferably one or more of 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, 157-triazabicyclo (4.4.0) dec-5-ene, tetramethylguanidine, triethylamine, tri-tert-butylamine, triethylenediamine, 4-dimethylaminopyridine, N-diisopropylethylamine, pyridine, sodium hydride, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate and potassium phosphate; when the second alkali compound is a plurality of the above, the proportion of different alkali compounds is not particularly limited, and any proportion can be adopted. In the invention, the molar ratio of the second base compound to the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I is preferably (1-5): 1, and more preferably (2-3): 1.
In the present invention, the kind and the amount of the second organic solvent are preferably the same as those of the first organic solvent, and are not described herein again.
In the present invention, the process of the second [2+1] cycloaddition reaction is preferably the same as the first [2+1] cycloaddition reaction, and will not be described herein.
In the present invention, the process of the first [2+1] cycloaddition reaction is represented by the following formula:
Figure BDA0003116946390000111
in the present invention, the chiral fluoroalkyl cyclopropane compound having the structure represented by the formula V is preferably
Figure BDA0003116946390000112
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Figure BDA0003116946390000121
Under the condition of nitrogen, dissolving o-trifluoromethylbenzenesulfonylhydrazide (30mmol) and a ketone compound trifluoromethylacetophenone (30mmol) in 40mL Ethyl Acetate (EA), then adding boron trifluoride diethyl etherate (45mmol), reacting the obtained material in an oil bath kettle at 40 ℃ overnight, after the reaction is finished, adding 40mL of saturated sodium chloride aqueous solution (the mass concentration is 1.33g/mL) into the obtained product, extracting with EA, drying the obtained extract with magnesium sulfate, concentrating under reduced pressure, and performing silica gel column chromatography on the obtained product to obtain trifluoromethylbenzenesulfonylhydrazone 1 a;
the trifluoromethylbenzenesulfonylhydrazone 1a (39.6mg, 0.1mmol) was added under nitrogen) Phenylacetylene 2a (20mg,0.2mmol) and a commercially available chiral metal catalyst Rh2(R-BTPCP)4(2mg,1 mol% relative to 1 a), DIPEA (33. mu.l, 0.2mmol) and 3mL of toluene were charged into a 10mL reaction flask, stirred at-40 ℃ for 12h, after completion of the reaction, the resulting product was filtered through Celite, the resulting filtrate was concentrated under reduced pressure, and after separation by silica gel column chromatography, compound 3a was obtained as a colorless oil (27.4mg, yield 95%).
Characterization of
Performing nuclear magnetic characterization on the compound 3a prepared in example 1, wherein the obtained spectrograms are respectively shown in figures 1-3; the characterization data obtained were:
1H-NMR(600MHz,CDCl3)δ7.65-7.63(m,2H),7.44-7.39(m,5H),7.29(t,J＝7.8Hz,2H),7.24(t,J＝7.2Hz,1H),7.14(q,J＝1.2Hz,1H).13C-NMR(150MHz,CDCl3)δ138.2,130.4,130.0,129.0,128.4,127.7,127.2,126.7(q,J＝278.0Hz),125.1,117.5(q,J＝2.1Hz),98.9(q,J＝2.7Hz),32.2(q,J＝35.4Hz).19F NMR(470MHz,CDCl3)δ-63.9.
high performance liquid chiral analysis was performed on compound 3a prepared in example 1 with the following data: chiralcel OD-H, 0% iPr-OH in hexane,1mL/min λ 230nm, tR 7.300min, major; tR 11.747min, minor.
Example 2
Figure BDA0003116946390000131
Under the condition of nitrogen, trifluoromethyl benzenesulfonylhydrazone 1a (39.6mg, 0.1mmol), styrene 2b (21mg,0.2mmol) and a chiral metal catalyst Rh are added2(R-PTAD)4(2mg,1 mol%), DIPEA (33. mu.l, 0.2mmol) and toluene (3 mL) were charged into a 10mL reaction flask, stirred at room temperature for 12 hours, after completion of the reaction, the resulting product was filtered through celite, the resulting filtrate was concentrated under reduced pressure, and after separation by silica gel column chromatography, Compound 3b was obtained as a colorless oil (25.4mg, yield 97%).
Characterization of
Performing nuclear magnetic characterization on the compound 3b prepared in example 2, wherein the obtained spectrograms are respectively shown in figures 4-6; the characterization data obtained were:
1H-NMR(600MHz,CDCl3)δ7.21-7.18(m,1H),7.16-7.12(m,4H),7.10-7.06(m,3H),6.79-6.76(m,2H),2.84(dd,J＝7.0Hz,J＝9.6Hz,1H),1.87(dd,J＝6.0Hz,J＝9.6Hz,1H),1.69-1.66(m,1H).13C-NMR(150MHz,CDCl3)δ135.6,132.5,131.5,128.1,127.93,127.89,127.8,126.4,125.8(q,J＝272.2Hz),35.8(q,J＝32.2Hz),25.6(q,J＝2.6Hz),14.6(q,J＝2.7Hz).19F NMR(470MHz,CDCl3)δ-69.8.
high performance liquid chiral analysis was performed on compound 3b prepared in example 2 with the following data: chiralcel OJ-H, 0% i-PrOH in hexane,0.7mL/min λ 230nm, tR 9.943min, major; tR 16.487min, minor.
Example 3
Figure BDA0003116946390000132
Dissolving o-trifluoromethyl benzenesulfonylhydrazide (30mmol) and a ketone compound trifluoromethyl p-phenylacetophenone (30mmol) in 40mL of Ethyl Acetate (EA) under the condition of nitrogen, then adding boron trifluoride diethyl etherate (45mmol), reacting the obtained material in an oil bath kettle at 40 ℃ overnight, adding 40mL of saturated sodium chloride aqueous solution (mass concentration of 1.33g/mL) into the obtained product after the reaction is finished, extracting with EA, drying the obtained extract with magnesium sulfate, concentrating under reduced pressure, and performing silica gel column chromatography on the obtained product to obtain trifluoromethyl benzenesulfonylhydrazone 1 b;
under the nitrogen condition, trifluoromethyl benzenesulfonylhydrazone 1b (47.2mg, 0.1mmol), cyclopentyne 2c (19mg,0.2mmol) and a chiral metal catalyst Rh are added2(R-BTPCP)4(2mg,1 mol%), DIPEA (33. mu.l, 0.2mmol) and toluene (3 mL) were charged into a 10mL reaction flask, stirred at-40 ℃ for 12 hours, after completion of the reaction, the resulting product was filtered through Celite, the resulting filtrate was concentrated under reduced pressure, and after separation by silica gel column chromatography, Compound 3c was obtained as a colorless oil (20.7mg, yield 63%).
Characterization of
Performing nuclear magnetic characterization on the compound 3c prepared in example 3, wherein the obtained spectrograms are respectively shown in figures 7-9; the characterization data obtained were:
1H-NMR(600MHz,CDCl3)δ7.57(d,J＝7.2Hz,2H),7.54(d,J＝7.8Hz,2H),7.42(t,J＝7.8Hz,2H),7.38(d,J＝7.8Hz,2H),7.33(t,J＝7.2Hz,1H),6.65(s,1H),3.05-3.01(m,1H),1.96-1.89(m,2H),1.69-1.58(m,6H).13C-NMR(150MHz,CDCl3)δ140.7,139.7,138.2,128.7,127.9,127.2,127.03,126.97,126.9(q,J＝275.0Hz),124.2,95.3(q,J＝3.3Hz),35.2,32.0(q,J＝34.7Hz),31.1,31.0,25.1,25.0.19F NMR(470MHz,CDCl3)δ-63.7.
high performance liquid chiral analysis was performed on compound 3c prepared in example 3 with the following data: chiralcel OZ-H, 0% iPr-OH in hexane,1mL/min λ 230nm, tR 5.413min, major; tR 6.397min, minor.
Example 4
Figure BDA0003116946390000141
Under the nitrogen condition, trifluoromethyl benzenesulfonylhydrazone 1b (47.2mg, 0.1mmol), styrene 2b (21mg,0.2mmol) and a chiral metal catalyst Rh are added2(R-PTAD)4(2mg,1 mol%), DIPEA (33 μ l,0.2mmol) and toluene (3 mL) were charged into a 10mL reaction flask, stirred at room temperature for 12 hours, after completion of the reaction, the resulting product was filtered with celite, the resulting filtrate was concentrated under reduced pressure, and after separation by silica gel column chromatography, compound 3d was obtained as a white solid (30.7mg, yield 91%).
Characterization of
Performing nuclear magnetic characterization on the compound 3d prepared in example 4, wherein the obtained spectrograms are respectively shown in figures 10-12; the characterization data obtained were:
mp:87-88℃；1H-NMR(600MHz,CDCl3)δ7.51(d,J＝6.6Hz,2H),7.40-7.37(m,4H),7.31(t,J＝7.5Hz,1H),7.19(d,J＝7.8Hz,2H),7.11-7.06(m,3H),6.82-6.81(m,2H),2.86(dd,J＝7.0Hz,J＝9.6Hz,1H),1.90(dd,J＝6.0Hz,J＝9.6Hz,1H),1.72-1.69(m,1H).13C-NMR(150MHz,CDCl3)δ140.8,140.4,135.5,132.8,130.5,128.7,127.95,127.89,127.40,127.0,126.6,126.5,125.9(q,J＝272.8Hz),35.5(q,J＝32.3Hz),25.7(q,J＝2.4Hz),14.7(q,J＝2.6Hz).19F NMR(470MHz,CDCl3)δ-69.7.
high performance liquid chiral analysis was performed on compound 3d prepared in example 4 with the following data: chiralcel OJ-H, 2% iPr-OH in hexane,1mL/min λ 230nm, tR 6.727min, major; tR 13.667min, minor.
Example 5
Figure BDA0003116946390000151
Under the condition of nitrogen, trifluoromethyl benzenesulfonylhydrazone 1a (39.6mg, 0.1mmol), 3-methoxy phenylacetylene 2d (26.4mg,0.2mmol) and a chiral metal catalyst Rh are added2(R-BTPCP)4(2mg,1 mol%), DIPEA (33. mu.l, 0.2mmol) and toluene (3 mL) were charged into a 10mL reaction flask, stirred at-40 ℃ for 12 hours, after completion of the reaction, the resulting product was filtered through Celite, the resulting filtrate was concentrated under reduced pressure, and after separation by silica gel column chromatography, Compound 3e was obtained as a colorless oil (20.3mg, yield 70%).
Characterization of
Performing nuclear magnetic characterization on the compound 3e prepared in example 5, wherein the obtained spectrograms are respectively shown in figures 13-15; the characterization data obtained were:
1H-NMR(600MHz,CDCl3)δ7.42(d,J＝7.8Hz,2H),7.34(t,J＝7.8Hz,1H),7.30(t,J＝7.8Hz,2H),7.25-7.22(m,2H),7.16-7.14(m,2H),6.96(dd,J＝2.4Hz,J＝8.4Hz,1H),3.81(s,3H).13C-NMR(150MHz,CDCl3)δ159.9,138.1,130.0,128.4,127.7,127.2,126.7(q,J＝275.9Hz),126.2,122.5,117.5,116.5,114.8,99.3(q,J＝2.4Hz),55.3,32.4(q,J＝35.0Hz).19F NMR(470MHz,CDCl3)δ-64.0.
high performance liquid chiral analysis was performed on compound 3e prepared in example 5 with the following data: chiralcel OD-H, 0.5% iPr-OH in hexane,1mL/min λ 230nm, tR 16.753min, major; tR 26.950min, minor.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A preparation method of a chiral fluoroalkyl ternary carbocyclic compound is characterized by comprising the following steps:
when the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropene compound:
mixing fluoroalkyl sulfonyl hydrazone derivatives with a structure shown in a formula I, alkyne derivatives with a structure shown in a formula II, a first chiral metal catalyst, a first alkali compound and a first organic solvent, and carrying out a first [2+1] cycloaddition reaction to obtain chiral fluoroalkyl cyclopropene compounds with a structure shown in a formula III;
when the chiral fluoroalkyl ternary carbocyclic compound is a chiral fluoroalkyl cyclopropane compound:
mixing fluoroalkyl sulfonyl hydrazone derivatives with a structure shown in a formula I, olefin derivatives with a structure shown in a formula IV, a second chiral metal catalyst, a second base compound and a second organic solvent, and performing a second [2+1] cycloaddition reaction to obtain chiral fluoroalkyl cyclopropane compounds with a structure shown in a formula V;
Figure FDA0003116946380000011
in the formulae I to V, R is1、R2、R3、R4、R5And R6Independently of each other is H, alkyl, C3～C27Cycloalkyl radical, C3～C9Heterocyclic group, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10Heteroaryl, substituted alkyl, substituted C3～C27Cycloalkyl, substituted C3～C9Heterocyclyl, substituted C2～C29Alkenyl, substituted C2～C29Alkynyl, substituted C6～C10Aryl or substituted C5～C10A heteroaryl group; the substituted substituent is independently halogen, nitryl, cyano, ester group, C1～C8Alkyl radical, C1～C8Fluoroalkyl radical C1～C4Alkoxy or C6～C10An aryl group;
the R isfIndependently is HCF2-、H2CF-、CF3-or has CnF2n+1Fluoroalkyl with a general structural formula, wherein n is 1-15.
2. The method of claim 1, wherein R is1Is phenyl or biphenyl; the R is2Is fluoromethylphenyl; the R is3Is hydrogen, phenyl, cyclopentyl or methoxyphenyl; the R is4Is hydrogen; the R is5Is phenyl or hydrogen; the R is6Is hydrogen.
3. The preparation method according to claim 1, wherein the molar ratio of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in formula I to the alkyne derivative with the structure shown in formula II is (1-5): 1; the molar ratio of the fluoroalkyl sulfonyl hydrazone derivative with the structure shown in the formula I to the olefin derivative with the structure shown in the formula IV is (1-5): 1.
4. The method of claim 1, wherein the first chiral metal catalyst and the second chiral metal catalyst are, independently:
Figure FDA0003116946380000021
wherein, X1、X2、X3、X4、X5、X6And X7Independently H, halogen, nitro, cyano, ester group, C1～C27Alkyl radical, C1～C9Fluoroalkyl radical, C1～C4Alkoxy radical, C2～C29Alkenyl radical, C2～C29Alkynyl, C6～C10Aryl radical, C5～C10A heteroaryl group containing N, O or S.
5. The preparation method according to claim 1 or 4, wherein the molar ratio of the first chiral metal catalyst and the second chiral metal catalyst to the trifluoromethylsulfonylhydrazone derivative having the structure represented by the formula I is independently (0.0001-0.2): 1.
6. The method according to claim 1, wherein the first base compound and the second base compound are independently one or more of 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, 157-triazabicyclo (4.4.0) dec-5-ene, tetramethylguanidine, triethylamine, tri-tert-butylamine, triethylenediamine, 4-dimethylaminopyridine, N-diisopropylethylamine, pyridine, sodium hydride, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate and potassium phosphate.
7. The preparation method according to claim 1 or 6, wherein the molar ratio of the first base compound to the fluoroalkyl sulfonyl hydrazone derivative having the structure represented by formula I is (1-5): 1.
8. The preparation method according to claim 1 or 6, wherein the molar ratio of the second base compound to the fluoroalkyl sulfonyl hydrazone derivative having the structure represented by formula I is (1-5): 1.
9. The preparation method according to claim 1, wherein the reaction temperature of the first [2+1] cycloaddition reaction and the reaction temperature of the second [2+1] cycloaddition reaction are independently-78-60 ℃ and the reaction time is independently 2-48 h.
10. The method according to claim 1, wherein the first organic solvent and the second organic solvent are independently one or more of toluene, acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, ethyl acetate and water.
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