A method for preparing trifluoromethyl-substituted pyrazolines

Abstract

The application provides a preparation method of a trifluoromethyl-substituted pyrazoline compound, and the preparation method comprises the following steps: reacting an olefin compound with 2,2,2-trifluorodiazoethane in the presence of a Lewis base to obtain the trifluoromethyl-substituted pyrazoline compound, and the reaction region selectivity of the application is good, and the yield is high.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis and relates to a preparation method of a trifluoromethyl-substituted pyrazoline compound. BACKGROUND

[0002] Synthesis of complex heterocycles containing fluorinated alkylidene groups has been a central goal of chemists in the pharmaceutical and agrochemical industries. Fluorinated pyrazolines, especially trifluoromethyl-substituted pyrazolines, have attracted much attention due to their significantly improved physicochemical and biological properties, such as lipophilicity, metabolic stability and bioavailability, compared to their parent molecules. Therefore, it is desirable to develop a simple and widely applicable synthetic protocol for the preparation of trifluoromethyl-substituted pyrazolines and potential precursor compounds.

[0003] 2,2,2-Trifluorodiazeneethane (CF3CHN2) can be prepared in situ, flow synthesis, N-sulfonylhydrazone surrogates under basic conditions or, has emerged as an attractive trifluoromethyl-containing building block in a variety of transformations, which can be classified as: metal carbene precursors, 1,3-dipoles, carbon nucleophiles / electrophiles, and nitrogen terminal electrophiles, according to the different roles they play in synthetic reactions. Mykhailiuk, Koenigs, Ma, Jamison and others reported the [3+2] cycloaddition reaction of CF3CHN2 with highly electrophilic olefin dipolar reagents, which showed a direct and efficient method for preparing trifluoromethyl-substituted pyrazolines, and generally electron-deficient olefins are effective electrophiles. However, unactivated olefins are still a gap in these studies.

[0004] In addition to electron-deficient olefins, in 2014, Ma and his colleagues reported a new method for highly regioselective cycloaddition of electron-deficient urenaic acid esters and ketones with trifluorodiazeneethane, and prepared a variety of 5-(trifluoromethyl) pyrazolines under mild reaction conditions. Since the current olefin dipolar reagent is limited to electron-deficient reagents, it is of great significance to study the cycloaddition reaction of CF3CHN2 and unactivated olefin dipolar reagents. SUMMARY

[0005] In view of the deficiencies of the prior art, the purpose of the present application is to provide a preparation method of a trifluoromethyl-substituted pyrazoline compound. The preparation method of the present application is mainly to obtain a trifluoromethyl-substituted pyrazoline compound by reacting an olefin compound with 2,2,2-trifluorodiazeneethane in the presence of a Lewis base, and the product has high selectivity and high yield.

[0006] To achieve this purpose, the technical scheme adopted by the present application is as follows:

[0007] In a first aspect, the present application provides a method for preparing a trifluoromethyl-substituted pyrazoline compound, the method comprising the following steps:

[0008] The olefin compound of Formula I is reacted with 2,2,2-trifluorodiazene ethane (CF3CHN2) in the presence of a Lewis base to obtain a trifluoromethyl-substituted pyrazoline compound of Formula II, as shown in the following reaction formula:

[0009]

[0010] wherein R 1 is selected from cyano, carboxylate, C6-C18arylcarbonyl, substituted or unsubstituted C6-C18aryl, substituted or unsubstituted C5-C18heteroaryl, substituted or unsubstituted C2-C4alkenyl, or substituted or unsubstituted C2-C4alkynyl;

[0011] R 2 is selected from hydrogen, substituted or unsubstituted C1-C5alkyl, or substituted or unsubstituted C6-C18aryl.

[0012] In the present application, the olefin compound of Formula I is reacted with 2,2,2-trifluorodiazene ethane (CF3CHN2) in the presence of a Lewis base to obtain a trifluoromethyl-substituted pyrazoline compound of Formula II, with high selectivity and high yield.

[0013] In the present application, the product is highly selectively generated as a trifluoromethyl-substituted pyrazoline compound of Formula II, while the isomer of Formula III has low selectivity and yield.

[0014] In the present application, the substituents in the substituted C6-C18aryl, substituted C5-C18heteroaryl, substituted C2-C4alkenyl, substituted C2-C4alkynyl, or substituted C1-C5alkyl are selected from halogen, C1-C5alkyl, C1-C5alkoxy, halogen-substituted C1-C5alkyl, phenyl, or acetoxy.

[0015] In the present application, the definition of the group includes a definition of the number of carbon atoms, and the defined range indicates that the number of carbon atoms in the group can be any integer within the range, for example, C6-C18aryl, which means that the number of carbon atoms in the aryl group can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, and so on.

[0016] Preferably, R 1 is selected from cyano, phenyl, pyridyl,

[0017] wherein R3 selected from C1-C5 alkyl, halogen, C1-C5 alkoxy, phenyl or halogen substituted C1-C5 alkyl, R 4 selected from hydrogen, halogen, C1-C5 alkyl or C1-C5 alkoxy, X is selected from hydrogen or halogen.

[0018] Preferably, R 2 selected from hydrogen, methyl, ethyl, phenyl, methoxy substituted phenyl or trifluoromethyl.

[0019] Preferably, the olefin compound of Formula I is any one of the following compounds:

[0020]

[0021]

[0022] wherein Me is methyl, t-Bu is tert-butyl, OAc is acetoxy, and OMe is methoxy.

[0023] Preferably, the 2,2,2-trifluorodiazoethane is dissolved in a stock solvent selected from any one of toluene, dichloromethane (DCM), dichloroethane (DCE), methyl tert-butyl ether (MTBE) or tetrahydrofuran (THF).

[0024] In the present application, since 2,2,2-trifluorodiazoethane is a gas, it is dissolved in a stock solvent to facilitate reaction operation.

[0025] Preferably, the 2,2,2-trifluorodiazoethane is dissolved in a stock solvent at a molar concentration of 1.0-2.0 M, for example 1.0 M, 1.3 M, 1.5 M, 1.8 M or 2.0 M.

[0026] Preferably, the molar ratio of the olefin compound of Formula I to 2,2,2-trifluorodiazoethane is 1:3-1:5, for example 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8 or 1:5.

[0027] Preferably, the Lewis base is selected from any one of 4-dimethylaminopyridine (DMAP), triethylamine (Et3N), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG) or tetramethylethylenediamine (TMEDA) or a combination of at least two thereof.

[0028] Preferably, the Lewis base is used in an amount of 5-20% of the molar amount of the olefin compound of formula I, such as 5%, 8%, 10%, 12%, 15%, 18% or 20%.

[0029] Preferably, the reaction is carried out without additional addition of solvent or the reaction is carried out with additional addition of solvent.

[0030] Preferably, the additional added solvent is selected from any one or a combination of at least two of dichloromethane, tetrahydrofuran or methyl tert-butyl ether, preferably methyl tert-butyl ether.

[0031] Preferably, the reaction is carried out at a temperature of 60-80°C, such as 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C, 78°C or 80°C.

[0032] Preferably, the reaction is carried out for a time of 10-72h, such as 10h, 15h, 18h, 20h, 24h, 27h, 30h, 34h, 36h, 40h, 44h, 48h, 50h, 55h, 58h, 60h, 62h, 64h, 68h, 70h or 72h.

[0033] In a second aspect, the present application provides a method for preparing a trifluoromethyl substituted pyrazoline compound, the method comprising the following steps:

[0034] reacting the olefin compound of formula III with 2,2,2-trifluorodiazomethane (CF3CHN2) in the presence of a Lewis base to obtain a trifluoromethyl substituted pyrazoline compound of formula IV, the reaction scheme being as follows:

[0035]

[0036] wherein R 5 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, R 6 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C18 aryl, the substituents of the substituted groups being selected from phenyl, phenoxy, phenylthio, carboxylate, C3-C10 cycloalkyl, amido or alkenyl sulfide.

[0037] Preferably, R 5 is selected from

[0038] methyl or cyclopropyl.

[0039] Preferably, R 6 is selected from hydrogen, methyl, cyclopropyl or phenyl.

[0040] Preferably, the olefin compound of Formula III is any one of the following compounds:

[0041] Preferably, the 2,2,2-trifluorodiazoethane is dissolved in a stock solvent selected from any one of toluene, dichloromethane (DCM), dichloroethane (DCE), methyl-tert-butyl ether (MTBE), or tetrahydrofuran (THF).

[0042] Preferably, the 2,2,2-trifluorodiazoethane is dissolved in a stock solvent at a molar concentration of 1.0-2.0 M, such as 1.0 M, 1.3 M, 1.5 M, 1.8 M, or 2.0 M.

[0043] Preferably, the molar ratio of the olefin compound of Formula III to 2,2,2-trifluorodiazoethane is 1 :3-1 :5, such as 1 :3, 1 :3.3, 1 :3.5, 1 :3.8, 1 :4, 1 :4.3, 1 :4.5, 1 :4.8, or 1 :5.

[0044] Preferably, the Lewis base is selected from any one of 4-dimethylaminopyridine (DMAP), triethylamine (Et3N), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7- ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), or tetramethylethylenediamine (TMEDA) or a combination of at least two thereof.

[0045] Preferably, the Lewis base is used in an amount of 5-20% of the molar amount of the olefin compound of Formula I, such as 5%, 8%, 10%, 12%, 15%, 18%, or 20%.

[0046] Preferably, the reaction is carried out without additional addition of solvent or with additional addition of solvent.

[0047] Preferably, the additional added solvent is selected from any one of dichloromethane, tetrahydrofuran, or methyl-tert-butyl ether or a combination of at least two thereof, preferably methyl-tert-butyl ether.

[0048] Preferably, the reaction is carried out at a temperature of 60-80 °C, such as 60 °C, 63 °C, 65 °C, 68 °C, 70 °C, 73 °C, 75 °C, 78 °C, or 80 °C.

[0049] Preferably, the reaction is carried out for a time of 10-72 h, such as 10 h, 15 h, 18 h, 20 h, 24 h, 27 h, 30 h, 34 h, 36 h, 40 h, 44 h, 48 h, 50 h, 55 h, 58 h, 60 h, 62 h, 64 h, 68 h, 70 h, or 72 h.

[0050] In a third aspect, the present application provides a method for preparing a trifluoromethyl substituted pyrazoline compound, the method comprising the steps of:

[0051] The olefin compound of Formula V is reacted with 2,2,2-trifluorodiazoethane (CF3CHN2) in the presence of a Lewis base to obtain the trifluoromethyl substituted pyrazoline compound of Formula VI and Formula VII, as shown in the following reaction scheme:

[0052]

[0053] wherein R is selected from

[0054] Preferably, the 2,2,2-trifluorodiazoethane is dissolved in a stock solvent selected from any one of toluene, dichloromethane (DCM), dichloroethane (DCE), methyl tert-butyl ether (MTBE) or tetrahydrofuran (THF).

[0055] Preferably, the 2,2,2-trifluorodiazoethane is dissolved in a stock solvent at a molar concentration of 1.0-2.0 M.

[0056] Preferably, the molar ratio of the olefin compound of Formula III to 2,2,2-trifluorodiazoethane is 1:3-1:5, such as 1:3, 1:3.3, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8 or 1:5.

[0057] Preferably, the Lewis base is selected from any one or a combination of at least two of 4-dimethylaminopyridine (DMAP), triethylamine (Et3N), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG) or tetramethylethylenediamine (TMEDA).

[0058] Preferably, the amount of the Lewis base is 5-20% of the molar amount of the olefin compound of Formula I, such as 5%, 8%, 10%, 12%, 15%, 18% or 20%.

[0059] Preferably, the reaction is carried out without additional addition of solvent or with additional addition of solvent.

[0060] Preferably, the additional solvent is selected from any one or a combination of at least two of dichloromethane, tetrahydrofuran or methyl tert-butyl ether, preferably methyl tert-butyl ether.

[0061] Preferably, the temperature of the reaction is 60-80°C, for example 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C, 78°C or 80°C.

[0062] Preferably, the time of the reaction is 10-72h, for example 10h, 15h, 18h, 20h, 24h, 27h, 30h, 34h, 36h, 40h, 44h, 48h, 50h, 55h, 58h, 60h, 62h, 64h, 68h, 70h or 72h.

[0063] Compared with the prior art, the present application has the following beneficial effects:

[0064] The present application provides a Lewis base catalyzed unactivated triazene cycloaddition strategy for the selective synthesis of a series of trifluoromethyl pyrazoline compounds with high yield. The reaction can be extended to the connection with drug molecules, scaffold diversification reactions of natural products and biologically active heterocycles, which is very attractive for drug chemistry research. These results expand the scope of CF3CHN2 cycloaddition reactions, in which unactivated olefins can successfully participate to produce nitrogen heterocycles. BRIEF DESCRIPTION OF DRAWINGS

[0065] Figure 1 Crystallographic diffraction structure of the Z configuration isomer of the product obtained for example 37.

[0066] Figure 2 Crystallographic diffraction structure of the E configuration isomer of the product obtained for example 37. DETAILED DESCRIPTION

[0067] The technical solutions of the present application are further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are only to help understand the present application and should not be regarded as specific limitations of the present application.

[0068] In the present application, part of the raw materials can be prepared according to the known literature method, and the preparation is specifically as follows:

[0069]

[0070] To a solution of allylphosphonic acid diethyl ester (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) under nitrogen atmosphere at 0 °C. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9: 1) as eluent to give (E)-1-(4-methoxyphenyl)butadiene.

[0071]

[0072] To a solution of allylphosphonic acid diethyl ester (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) under nitrogen atmosphere at 0 °C. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9: 1) as eluent to give (E)-1-(4-methoxyphenyl)butadiene.

[0073]

[0074] To a solution of allylphosphonic acid diethyl ester (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) under nitrogen atmosphere at 0 °C. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9: 1) as eluent to give (E)-1-(4-methoxyphenyl)butadiene.

[0075]

[0076] To a stirred solution of diethyl allylphosphonate (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride solution and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9:1) as eluent to give (E)-1-(2-bromo-4,5-methoxyphenyl)butadiene.

[0077]

[0078] To a stirred solution of diethyl allylphosphonate (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride solution and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9:1) as eluent to give (E)-1-(2-bromo-4,5-methoxyphenyl)butadiene.

[0079]

[0080] To a stirred solution of diethyl allylphosphonate (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride solution and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9:1) as eluent to give (E)-1-(2-bromo-4,5-methoxyphenyl)butadiene.

[0081]

[0082] To a stirred solution of allylphosphonic acid diethyl ester (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) under nitrogen at 0 °C. After stirring for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9:1) as eluent to give (E)-1-(1-pyridinyl)butadiene.

[0083]

[0084] To a stirred solution of allylphosphonic acid diethyl ester (3.0 mmol, 1.5 eq) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 eq) under nitrogen at 0 °C. After stirring for 15 min, a solution of 2-phenylacetaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9:1) as eluent to give (E)-1-phenyl-2,4-pentadiene.

[0085]

[0086] To a stirred suspension of methyltriphenylphosphonium bromide (1.2 eq) in tetrahydrofuran (0.15 M) was added tert-butyllithium (1.2 eq, 2.4 M in n-hexane) slowly at 0 °C. The mixture was allowed to warm to room temperature and stirred for 30 min to give a deep red solution. A solution of 10 mL of α-bromocinnamaldehyde (10 mmol) in tetrahydrofuran was then added dropwise at room temperature and stirred overnight. An equal volume of petroleum ether was added to the reaction mixture and stirred for a further hour. The reaction was filtered through a small plug of Celite and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate) to give (Z)-(2-bromobut-1,3-dien-1-yl)benzene.

[0087]

[0088] To a solution of allyl phosphonate diethyl ester (3.0 mmol, 1.5 equiv) in tetrahydrofuran (25 mL) was added sodium hydride (72 mg, 3.0 mmol, 1.5 equiv) with stirring under a nitrogen atmosphere. After stirring at 0 °C for 15 min, a solution of 4-methoxybenzaldehyde (2.0 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction was stirred at 0 °C until completion (monitored by TLC). The reaction was then quenched and extracted with aqueous ammonium chloride and ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (9: 1) as eluent to give (Z)-3-phenylacrylonitrile.

[0089]

[0090] Phosphotungstic acid hydrate (0.253 g, 0.05 equiv) was added to a solution of dihydroartemisinin (0.5 g, 1.76 mmol) in dry dichloromethane (20 mL) and the reaction mixture was stirred at room temperature for 5 min. Allyl alcohol (70 mg, 2.18 mmol, 1.25 equiv) was added to the mixture and the reaction mixture was further stirred for 3 h. The catalyst was removed by filtration and the filtrate was concentrated. The crude product was subjected to TLC chromatography and the residue was purified by column chromatography on silica gel to give 10-allyloxy-3,6,9-trimethyldecahydro-12H-3,12-epoxy[l,2]dioxepino[4,3-i]isochromene.

[0091]

[0092] Cholesterol (3.86 g, 10 mmol), sodium hydride (0.288 g, 30.00 mmol) and allyl bromide (1.04 mL, 12 mmol) were dissolved in tetrahydrofuran (30.00 mL) and the mixture was refluxed for 12 h. It was then cooled to room temperature and the solvent was removed in vacuo. The residue was quenched with dichloromethane and saturated brine and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with hexane and concentrated in vacuo to give the allyl cholesterol ether.

[0093]

[0094] Oleanolic acid (3.86 g, 10 mmol), sodium hydride (0.288 g, 30.00 mmol) and allyl bromide (1.04 mL, 12 mmol) were dissolved in tetrahydrofuran (30.00 mL) and the mixture was refluxed for 12 hours. It was then cooled to room temperature and the solvent was removed in vacuo. The residue was quenched with dichloromethane and saturated brine and the aqueous layer was extracted with dichloromethane (2 x 10 mL), the combined organic extracts were washed with brine (2 x 10 mL), dried and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel and concentrated in vacuo to give the allyl oleanolic acid ether.

[0095]

[0096] A solution of 3-hydroxyflavone (1.00 g, 4.20 mmol, 1.0 equiv) in dry acetone (100 mL) was added to a solution of allyl bromide (0.54 mL, 6.30 mmol, 1.5 equiv) at room temperature, followed by potassium carbonate (870.0 mg, 6.30 mmol, 1.5 equiv). The temperature was slowly increased to 65 °C and the reaction mixture was stirred overnight. The mixture was then cooled to room temperature and 30 mL of diethyl ether was added. After the salts were filtered through a pad of celite, the solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel to give the allyl flavone ether.

[0097]

[0098] A solution of furanose (1.00 g, 3.84 mmol) in N,N-dimethylformamide (1.5 mL) and allyl bromide (0.487 mL, 5.76 mmol) was added to a cold solution (0 °C) of sodium hydride (60% in oil; 184 g, 4.60 mmol) in N,N-dimethylformamide (2.34 mL). After the reaction mixture was stirred at 40 °C for 1 h, another portion of sodium hydride (60% in oil; 0.046 g, 0.958 mmol) was added at 0 °C. After the mixture was stirred at 40 °C for 3 h, the reaction was quenched by the addition of methanol (0.06 mL) at 0 °C. The mixture was diluted with water (4 mL) and extracted with ethyl acetate (4 x 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was co-evaporated with toluene to give 3-0-allyl- 1,2:5,6-di-0-isopropylidene-α-D-glucopyranoside.

[0099]

[0100] Into a 50 mL round bottom flask equipped with a stir bar was added indole (234 mg, 2.00 mmol) and crushed potassium hydroxide (336 mg, 6.00 mmol). Then, dimethyl sulfoxide (5 mL) was added to the flask and the solution was stirred at room temperature for 15 minutes. Next, allyl bromide (484 mg, 4.00 mmol) was added. The reaction mixture was further stirred at room temperature for 18 hours. Then, the reaction mixture was diluted with dichloromethane (15 mL) and washed with water (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 1-allyl-1H-indole.

[0101]

[0102] To a solution of acridinone (635 mg, 3.25 mmol) in tetrahydrofuran (7.0 mL) was added 6N aqueous potassium hydroxide (7.0 mL) and tetrabutylammonium bromide (250 mg, 0.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then allyl bromide (1 mL, 11.55 mmol) was added to the resulting suspension. After stirring at room temperature for 16 h, the tetrahydrofuran was removed by rotary evaporator and the resulting aqueous layer was further extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with deionized water, dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by flash column chromatography to yield 10-allyl-9(10H)-acridinone.

[0103]

[0104] The imino dibenzyl (2.92 g, 14.9 mmol, 1 eq.) dissolved in N,N-dimethylformamide (35 mL) was reacted with sodium hydride (2.36 g, 59.7 mmol, 4 eq.) and allyl bromide (3.86 mL, 44.6 mmol, 3 eq.) and the product was purified by column chromatography (pentane) to yield the target compound 5-allyl-10,11-dihydro-5H-dibenzo[b,f]azepine.

[0105] In the present invention, other raw materials can be purchased.

[0106] Example 1

[0107] In this example, a method for preparing trifluoromethylated pyrazoline is provided, and the reaction formula is as follows:

[0108]

[0109] The specific steps are as follows:

[0110] In a dry sealed tube was charged with styrene la (0.2 mmol, 1.0 equiv), a solution of CF3CHN2(0.75 mmol, 3.75 equiv) in anhydrous toluene (0.5 mL, referred as stock solvent). Subsequently, the basic material DMAP (0.06 mmol, 20 mol%) was added. The resulting yellow solution was left to react at 60 °C under stirring for 12 h. After the end of the reaction, the solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (pentane / ethyl acetate 50:1 to 5:1) to give 2-phenyl-5-trifluoromethylpyrazoline.

[0111] Chromatographic separation gave product 3a (22.7 mg) and 3a' (8.8 mg) in 54% and 21% yield, respectively.

[0112] The obtained product 3a was structurally characterized,

[0113] 1 H NMR (400 MHz, DMSO-d6): d = 7.79 - 7.77 (m, 1H), 7.65 (t, J = 1.8 Hz, 1H), 7.63 (t, J = 1.9 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.38 - 7.33 (m, 1H), 4.56 - 4.44 (m, 1H), 3.46 (dd, J = 17.3, 12.2 Hz, 1H), 3.09 (dd, J = 17.3, 9.0 Hz, 1H) ppm.

[0114] 13 C NMR (151 MHz, DMSO-d6): d = 149.7, 132.1, 128.9, 128.7, 126.1 (q, JC-F = 277.8 Hz), 125.9, 59.2 (q, JC-F = 28.7 Hz), 33.3 ppm.

[0115] 19 F NMR (376 MHz, DMSO-d6): d = -74.65 (d, JC-F = 7.5 Hz, 3F) ppm.

[0116] HRMS (ESI): calcd for C10H10N2F3 [M+H]+: 215.0634, found 215.0631.

[0117] Example 2

[0118] Differently from Example 1, the basic material DMAP was replaced with an equimolar amount of triethylamine (Et3N) in Example 1, the rest was the same as Example 1. The yield of products 3a and 3a' was 76% and 15%, respectively.

[0119] Example 3

[0120] Example 1 except that the basic material DMAP in Example 1 was replaced by an equimolar amount of DIPEA, and the rest was the same as Example 1. The yield of products 3a and 3a' was 34% and 55%, respectively.

[0121] Example 4

[0122] Example 1 except that the basic material DMAP in Example 1 was replaced by an equimolar amount of DBU, and the rest was the same as Example 1. The yield of products 3a and 3a' was 80% and 16%, respectively.

[0123] Example 5

[0124] Example 1 except that the basic material DMAP in Example 1 was replaced by an equimolar amount of TMG, and the rest was the same as Example 1. The yield of products 3a and 3a' was 74% and 20%, respectively.

[0125] Example 6

[0126] Example 1 except that the basic material DMAP in Example 1 was replaced by an equimolar amount of TMEDA, and the rest was the same as Example 1. The yield of products 3a and 3a' was 77% and 12%, respectively.

[0127] Example 7

[0128] Example 4 except that the stock solvent in Example 4 was replaced by an equal volume of anhydrous DCM, and the yield of products 3a and 3a' was 64% and 27%, respectively.

[0129] Example 8

[0130] Example 4 except that the stock solvent in Example 4 was replaced by an equal volume of anhydrous DCE, and the yield of products 3a and 3a' was 67% and 30%, respectively.

[0131] Example 9

[0132] Example 4 except that the stock solvent in Example 4 was replaced by an equal volume of anhydrous MTBE, and the yield of products 3a and 3a' was 81% and 10%, respectively.

[0133] Example 10

[0134] Example 4 except that the stock solvent in Example 4 was replaced by an equal volume of anhydrous THF, and the yield of products 3a and 3a' was 55% and 36%, respectively.

[0135] Example 11

[0136] In this example, a method for preparing trifluoromethylated pyrazolines is provided, the specific steps are as follows:

[0137] In a dry sealed tube, was charged with styrene la (0.2 mmol, 1.0 equiv), a solution of CF3CHN2(0.75 mmol, 3.75 equiv) in anhydrous toluene (0.5 mL, referred to as stock solvent). Subsequently, the basic material DBU (0.06 mmol, 20 mol%) and the reaction solvent anhydrous DCM (0.25 mL) were added. The resulting yellow solution was left to react at 60 °C under stirring for 12 h. After the end of the reaction, the solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (pentane / ethyl acetate 50:1 to 5:1) to give the products 3a and 3a' in 56% and 31% yield, respectively.

[0138] Example 12

[0139] The difference with Example 11 is that the reaction solvent anhydrous DCM in Example 11 was replaced by an equal volume of THF, obtaining products 3a and 3a' in 67% and 24% yield, respectively.

[0140] Example 13

[0141] The difference with Example 11 is that the reaction solvent anhydrous DCM in Example 11 was replaced by an equal volume of MTBE, obtaining products 3a and 3a' in 86% and 5% yield, respectively.

[0142] Example 14

[0143] The difference with Example 13 is that the reaction temperature in Example 13 was adjusted to 80 °C, obtaining products 3a in 95% yield and 3a' in traces.

[0144] Example 15

[0145] The difference with Example 13 is that the reaction temperature in Example 13 was adjusted to 40 °C, obtaining products 3a in 39% yield and 3a' in traces.

[0146] Example 16

[0147] The difference with Example 14 is that the amount of DBU in Example 14 was adjusted to 0.03 mmol (10 mol%), obtaining products 3a in 83% yield and 3a' in traces.

[0148] Comparative Example 1

[0149] The difference with Example 1 is that in this comparative example no basic material was added, obtaining products 3a and 3a' in 28% and 3% yield, respectively.

[0150] The reaction conditions of Examples 1-16 and Comparative Example 1 are summarized in Table 1.

[0151] Table 1

[0152]

[0153]

[0154] As can be seen from Examples 1-16 and Comparative Example 1 above, the use of Lewis base can promote the reaction to have higher selectivity of product 3a, and can improve the efficiency and selectivity of the reaction. Moreover, using toluene as the stock solvent, DBU as the basic substance, MTBE as the reaction solvent, and reacting at 80°C can have higher selectivity and yield of product 3a (the yield reaches 95%).

[0155] Example 17

[0156] In this example, a method for preparing trifluoromethylated pyrazoline is provided, and the reaction formula is as follows:

[0157]

[0158] The specific steps are as follows:

[0159] In a dry sealed tube, a solution of styrene 1b (0.2 mmol, 1.0 equivalent), CF3CHN2(0.75 mmol, 3.75 equivalents) in anhydrous toluene (0.5 mL, referred to as stock solvent) was charged. Subsequently, the basic substance DBU (0.06 mmol, 20 mol%) and the reaction solvent anhydrous MTBE (0.25 mL) were added. The resulting yellow solution was allowed to react at 80°C for 10 hours under stirring. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography (pentane / ethyl acetate volume ratio 50:1 to 5:1) to obtain product 3b (40.1 mg) with a yield of 88%.

[0160] The obtained product was structurally characterized,

[0161] 1 H NMR (400 MHz, DMSO-d6): δ = 7.91 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 6.43 (d, J = 6.4 Hz, 1H), 4.58 (dd, J = 14.0, 6.7 Hz, 1H), 3.43-3.36 (m, 1H), 3.18 (dd, J = 17.0, 2.7 Hz, 1H), 2.39 (s, 3H) ppm.

[0162] 13C NMR (101 MHz, DMSO-d6): δ = 144.1, 134.1, 129.4, 128.4, 126.0 (q, JC-F = 282.8 Hz), 65.3 (q, JC-F = 30.3 Hz), 38.8, 21.3 ppm.

[0163] 19 F NMR (376 MHz, DMSO-d6): δ = -77.91 (d, JC-F = 7.5 Hz, 3F) ppm.

[0164] HRMS (ESI): calcd for C11H12N2F3 [M+H]+: 229.0795, found 229.0789.

[0165] Examples 18-49

[0166] Different from example 17, different vinyl monomers were used, and different reaction time was used to prepare the corresponding products. The rest of the material amount and reaction temperature were the same as example 17, and the specific operation was the same as shown in table 2.

[0167] Table 2

[0168]

[0169]

[0170]

[0171]

[0172] As can be seen from Table 2, aromatic olefins with electron-donating (e.g. methyl, tert-butyl and methoxy) or electron-withdrawing (e.g. trifluoromethyl and halide) groups at random positions of the aryl ring all reacted smoothly to give the corresponding 5-trifluoromethylpyrazolines in good to excellent yields. In general, aromatic olefins containing electron-donating groups were slightly more reactive than aromatic olefins with electron-withdrawing groups. Both bulky olefins (e.g. 2-vinylnaphthalene and 9-vinylanthrance) and heterocyclic olefins (e.g. 2-vinylbenzo[b]thiophene and 4-vinylpyridine) also adapted to the reaction to give the products in 73-90% yields. Strongly electron-withdrawing methyl acrylate also adapted to the reaction to provide the desired product in 90% yield. In addition to the explored olefins, conjugates 1,3-dienes / alkenynes also underwent smoothly and regioselectively the cycloaddition at the terminal C=C bond to give the target products 5-trifluoromethylpyrazolines (e.g. Examples 34-43) in 57-91% yields, however, the Z / E selectivity of the product of Example 37 can be due to the electron-rich effect of the conjugated system. Furthermore, various 1,2-disubstituted internal olefins were also examined (Examples 44-49). As expected, in addition to the internal olefins with at least one electron-withdrawing group, the unactivated trans-β-methylstyrene also provided the corresponding product in moderate yield.

[0173] Meanwhile we have unambiguously confirmed the Z / E structure and the relative stereochemical nature of the product of Example 37 by X-ray diffraction analysis, the results of which are shown in Figure 1 and Figure 2

[0174] The structural characterization data of the products of Examples 18-49 are as follows:

[0175] Example 18:

[0176] 1 H NMR (600 MHz, DMSO-d6): δ = 7.94 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 6.43 (d, J = 6.3 Hz, 1H), 4.57 (dd, J = 13.8, 6.7 Hz, 1H), 3.39 (dd, J = 16.9, 9.3 Hz, 1H), 3.18 (dd, J = 16.9, 2.8 Hz, 1H), 1.31 (d, J = 5.8 Hz, 9H) ppm.

[0177] 13 C NMR (101 MHz, DMSO-d6): δ = 156.7, 134.1, 128.3, 126.0 (q, J = 272.0 Hz), 125.9 (q, J = 272.0 Hz), 123.9 (q, J = 272.0 Hz), 123.8 (q, J = 272.0 Hz), 123.7 (q, J = 272.0 Hz), 123.6 (q, J = 272.0 Hz), 123.5 (q, J = 272.0 Hz), 123.4 (q, J = 272.0 Hz), 123.3 (q, J = 272.0 Hz), 123.2 (q, J = 272.0 Hz), 123.1 (q, J = 272.0 Hz), 123.0 (q, J = 272.0 Hz), 122.9 (q, J = 272.0 Hz), 122.8 (q, J = 272.0 Hz), 122.7 (q, J = 272.0 Hz), 122.6 (q, J = 272.0 Hz), 122.5 (q, J = 272.0 Hz), 122.4 (q, J = 272.0 Hz), 122.3 (q, J = 272.0 Hz), 122.2 (q, J = 272.0 Hz), 122.1 (q, J = 272.0 Hz), 122.0 (q, J = 272.0 Hz), 121.9 (q, J = 272.0 Hz), 121.8 (q, J = 272.0 Hz), 121.7 (q, J = 272.0 Hz), 121.6 (q, J = 272.0 Hz), 121.5 (q, J = 272.0 Hz), 121.4 (q, J = 272.0 Hz), 121.3 (q, J = 272.0 Hz), 121.2 (q, J = 272.0 Hz), 121.1 (q, J = 272.0 Hz), 121.0 (q, J = 272.0 Hz), 120.9 (q, J = 272.0 Hz), 120.8 (q, J = 272.0 Hz), 120.7 (q, J = 272.0 Hz), 120.6 (q, J = 272.0 Hz), 120.5 (q, J = 272.0 Hz), 120.4 (q, J = 272.0 Hz), 120.3 (q, J = 272.0 Hz), 120.2 (q, J = 272.0 Hz), 120.1 (q, J = 272.0 Hz), 120.0 (q, J = 272.0 Hz), 119.9 (q, J = 272.0 Hz), 119.8 (q, J = 272.0 Hz), 119.7 (q, J = 272.0 Hz), 119.6 (q, J = 272.0 Hz), 119.5 (q, J = 272.0 Hz), 119.4 (q, J = 272.0 Hz), 119.3 (q, J = 272.0 Hz), 119.2 (q, J = 272.0 Hz), 119.1 (q, J = 272.0 Hz), 119.0 (q, J = 272.0 Hz), 118.9 (q, J = 272.0 Hz), 118.8 (q, J = 272.0 Hz), 118.7 (q, J = 272.0 Hz), 118.6 (q, J = 272.0 Hz), 118.5 (q, J = 272.0 Hz), 118.4 (q, J = 272.0 Hz), 118.3 (q, J = 272.0 Hz), 118.2 (q, J = 272.0 Hz), 118.1 (q, J = 272.0 Hz), 118.0 (q, J = 272.0 Hz), 117.9 (q, J = 272.0 Hz), 117.8 (q, J = 272.0 Hz), 117.7 (q, J = 272.0 Hz), 117.6 (q, J = 272.0 Hz), 117.5 (q, J = 272.0 Hz), 117.4 (q, J = 272.0 Hz), 117.3 (q, J = 272.0 Hz), 117.2 (q, J = 272.0 Hz), 117.1 (q, J = 272.0 Hz), 117.0 (q, J = 272.0 Hz), 116.9 (q, J = 272.0 Hz), 116.8 (q, J = 272.0 Hz), 116.7 (q, J = 272.0 Hz), 116.6 (q, J = 272.0 Hz), 116.5 (q, J = 272.0 Hz), 116.4 (q, J = 272.0 Hz), 116.3 (q, J = 272.0 Hz), 116.2 (q, J = 272.0 Hz), 116.1 (q, J = 272.0 Hz), 116.0 (q, J = 272.0 Hz), 115.9 (q, J = 272.0 Hz), 115.8 (q, J = 272.0 Hz), 115.7 (q, J = 272.0 Hz), 115.6 (q, J = 272.0 Hz), 115.5 (q, J = 272.0​C-F = 283.4 Hz), 125.7, 65.3 (q, J = 31.3 Hz), 38.9, 35.0, 30.9 ppm. C-F = 283.4 Hz), 125.7, 65.3 (q, J = 31.3 Hz), 38.9, 35.0, 30.9 ppm.

[0178] 19 F NMR (376 MHz, DMSO-d6): δ = -77.91 (d, J = 7.5 Hz, 3F) ppm. C-F = 283.4 Hz), 125.7, 65.3 (q, J = 31.3 Hz), 38.9, 35.0, 30.9 ppm.

[0179] HRMS (ESI): calcd for C 14 H 18 N2F3[M+H] + : 271.1562, found 271.1558.

[0180] Example 19:

[0181] 1 H NMR (600 MHz, DMSO-d6): δ = 7.98 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.42 (d, J = 6.5 Hz, 1H), 4.56 (dd, J = 14.0, 6.9 Hz, 1H), 3.85 (s, 3H), 3.39 - 3.35 (m, 1H), 3.12 (dd, J = 16.9, 2.4 Hz, 1H) ppm.

[0182] 13 C NMR (151 MHz, DMSO-d6): δ = 163.6, 130.7, 129.6, 126.1 (q, J = 283.9 Hz), 114.1, 65.4 (q, J = 31.7 Hz), 55.7, 38.6 ppm. C-F = 283.4 Hz), 125.7, 65.3 (q, J = 31.3 Hz), 38.9, 35.0, 30.9 ppm. C-F = 283.4 Hz), 125.7, 65.3 (q, J = 31.3 Hz), 38.9, 35.0, 30.9 ppm.

[0183] 19 F NMR (376 MHz, DMSO-d6): δ = -77.91 (d, J = 7.5 Hz, 3F) ppm. C-F = 283.4 Hz), 125.7, 65.3 (q, J = 31.3 Hz), 38.9, 35.0, 30.9 ppm.

[0184] HRMS (ESI): calcd for C 11 H 12 ON2F3[M+H] + : 245.0896, found 245.0895.

[0185] Example 20: 1H NMR (400 MHz, DMSO-d6): δ = 7.77 (d, J = 4.4 Hz, 1H), 7.47 - 7.44 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 4.54 - 4.46 (m, 1H), 3.45 (dd, J = 17.3, 12.2 Hz, 1H), 3.09 (dd, J = 17.3, 9.0 Hz, 1H), 2.33 (s, 3H) ppm.

[0186] 13 C NMR (151 MHz, DMSO-d6): δ = 149.8, 137.9, 132.0, 129.6, 128.6, 126.1 (q, J C-F = 283.9 Hz), 126.5, 123.1, 59.2 (q, J C-F = 30.2 Hz), 33.4, 21.1 ppm.

[0187] 19 F NMR (376 MHz, DMSO-d6): δ = -74.73 (d, J C-F = 7.5 Hz, 3F) ppm.

[0188] HRMS (ESI): calcd for C 11 H 12 N2F3[M+H] + : 229.0792, found 229.0787.

[0189] Example 21: 1 H NMR (400 MHz, DMSO-d6): δ = 7.85 (s, 1H), 7.42 - 7.40 (m, 1H), 7.26 - 7.23 (m, 3H), 4.47 - 4.41 (m, 1H), 3.48 (dd, J = 17.1, 12.0 Hz, 1H), 3.16 (dd, J = 17.1, 9.0 Hz, 1H), 2.48 (s, 3H) ppm.

[0190] 13 C NMR (151 MHz, DMSO-d6): δ = 150.5, 136.5, 131.4, 130.9, 128.7, 128.2, 126.1 (q, J C-F = 277.8 Hz), 126.0, 58.6 (q, J C-F = 28.7 Hz), 35.5, 22.9 ppm.

[0191] 19F NMR (376 MHz, DMSO-d6): δ = -74.57 (d, J = 7.5 Hz, 3F) ppm. C-F = 7.5 Hz, 3F) ppm.

[0192] HRMS (ESI): calcd for C 11 H 12 N2F3[M+H] + : 229.0790, found 229.0786.

[0193] Example 22: 1 H NMR (400 MHz, DMSO-d6): δ = 8.05 - 8.01 (m, 2H), 7.64 - 7.60 (m, 2H), 6.45 (d, J = 6.4 Hz, 1H), 4.63 - 4.52 (m, 1H), 3.43 (dd, J = 17.2, 9.3 Hz, 1H), 3.24 (dd, J = 17.2, 2.7 Hz, 1H) ppm.

[0194] 13 C NMR (101 MHz, DMSO-d6): δ = 138.6, 135.2, 130.3, 129.0, 125.9 (q, J C-F = 277.8 Hz), 65.2 (q, J C-F = 31.3 Hz), 39.10 ppm.

[0195] 19 F NMR (376 MHz, DMSO-d6): δ = -77.94 (d, J C-F = 7.5 Hz, 3F) ppm.

[0196] HRMS (ESI): calcd for C 10 H9 N2ClF3[M+H] + : 249.0246, found 249.0240.

[0197] Example 23: 1 H NMR (400 MHz, DMSO-d6): δ = 7.96 - 7.93 (m, 2H), 7.78 - 7.75 (m, 2H), 6.47 (d, J = 6.4 Hz, 1H), 4.62 - 4.52 (m, 1H), 3.45 - 3.21 (m, 1H), 3.24 (dd, J = 17.2, 2.7 Hz, 1H) ppm.

[0198] 13C NMR (101 MHz, DMSO-d6): δ = 135.5, 133.0, 132.0, 130.2, 127.9, 129.0 (q, J = 32.3 Hz), 126.6, 125.9 (q, J = 4.0 Hz), 124.6 (q, J = 272.6 Hz), 59.9 (q, J = 30.3 Hz), 33.2 ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm.

[0199] 19 F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm.

[0200] HRMS (ESI): calcd for C 10 H9N2F6[M+H] + : 283.0678, found 283.0672.

[0201] Example 24: 1 H NMR (600 MHz, DMSO-d6): δ = 8.14 (d, J = 3.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 4.61 - 4.56 (m, 1H), 3.51 (dd, J = 17.3, 12.4 Hz, 1H), 3.17 (dd, J = 17.3, 9.0 Hz, 1H) ppm.

[0202] 13 C NMR (101 MHz, DMSO-d6): δ = 135.5, 133.0, 132.0, 130.2, 127.9, 129.0 (q, J = 32.3 Hz), 126.6, 125.9 (q, J = 4.0 Hz), 124.6 (q, J = 272.6 Hz), 59.9 (q, J = 30.3 Hz), 33.2 ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm.

[0203] 19 F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -61.12 (s, 3F), -77.81 (d, J = 7.5 Hz, 3F) ppm.

[0204] HRMS (ESI): calcd for C 11 H9N2F6[M+H] + : 283.0678, found 283.0672.

[0205] Example 25:1 H NMR (400 MHz, DMSO-d6): δ = 7.83 (d, J = 4.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 4.59 - 4.47 (m, 1H), 3.47 (dd, J = 17.3, 12.2 Hz, 1H), 3.12 (dd, J = 17.3, 9.0 Hz, 1H), 2.28 (s, 3H) ppm.

[0206] 13 C NMR (151 MHz, DMSO-d6): δ = 169.3, 150.9, 149.2, 129.8, 127.0, 126.1 (q, J C-F = 277.8 Hz), 122.2, 59.4 (q, J C-F = 28.7 Hz), 33.4, 20.9 ppm.

[0207] 19 F NMR (376 MHz, DMSO-d6): δ = -74.82 (d, J C-F = 7.5 Hz, 3F) ppm.

[0208] HRMS (ESI): calcd for C 12 H 12 O2N2F3 [M+H] + : 273.0845, found 273.0840.

[0209] Example 26: 1 H NMR (400 MHz, DMSO-d6): δ = 8.11 - 8.09 (m, 2H), 7.87 - 7.85 (m, 2H), 7.78 - 7.76 (m, 2H), 7.54 - 7.51 (m, 2H), 7.47 - 7.43 (m, 1H), 6.47 (d, J = 6.3 Hz, 1H), 4.64 - 4.57 (m, 1H), 3.51 - 3.44 (m, 1H), 3.27 (dd, J = 17.0, 2.8 Hz, 1H) ppm.

[0210] 13 C NMR (151 MHz, DMSO-d6): δ = 145.3, 139.3, 135.7, 129.6, 129.4, 128.9, 127.5, 127.4, 127.3, 126.3 (q, J C-F = 268.8 Hz), 65.3 (q, J C-F = 30.2 Hz), 39.4.

[0211] 19 F NMR (376 MHz, DMSO-d6): δ = -77.89 (d, J = 7.5 Hz, 3F) ppm. C-F

[0212] HRMS (ESI): calcd for C 16 H 14 N2F3[M+H] + : 291.1231, found 291.1226.

[0213] Example 27: 1 H NMR (400 MHz, DMSO-d6): δ = 7.98 (s, 1H), 7.64 (s, 1H), 7.60 - 7.58 (m, 1H), 7.44 - 7.38 (m, 2H), 4.55 - 4.53 (m, 1H), 3.45 (dd, J = 17.4, 12.3 Hz, 1H), 3.13 (dd, J = 17.4, 9.0 Hz, 1H) ppm.

[0214] 13 C NMR (151 MHz, DMSO-d6): δ = 148.4, 134.2, 133.6, 130.6, 128.5, 125.9 (q, J = 277.8 Hz), 125.4, 124.4, 59.5 (q, J = 28.7 Hz), 33.1 ppm. C-F C-F

[0215] 19 F NMR (376 MHz, DMSO-d6): δ = -74.81 (d, J = 7.5 Hz, 3F) ppm. C-F

[0216] HRMS (ESI): calcd for C 10 H9 N2ClF3[M+H] + : 249.0244, found 249.0241.

[0217] Example 28: 1 H NMR (400 MHz, DMSO-d6): δ = 7.98 (d, J = 4.0 Hz, 1H), 7.65 - 7.62 (m, 1H), 7.51 - 7.48 (m, 1H), 7.41 - 7.35 (m, 2H), 4.61 - 4.49 (m, 1H), 3.54 (dd, J = 17.4, 12.1 Hz, 1H), 3.24 (dd, J = 17.4, 9.0 Hz, 1H) ppm.​​​​

[0218] 13 C NMR (151 MHz, DMSO-d6): δ = 148.0, 131.1, 131.0, 130.7, 130.4, 130.2, 127.4, 125.9 (q, J C-F = 277.8 Hz), 59.6 (q, J C-F = 30.2 Hz), 35.7 ppm.

[0219] 19 F NMR (376 MHz, DMSO-d6): δ = -74.76 (d, J C-F = 7.5 Hz, 3F) ppm.

[0220] HRMS (ESI): calcd for C 10 H9 N2ClF3[M+H] + : 249.0245, found 249.0240.

[0221] Example 29:

[0222] 1 H NMR (600 MHz, DMSO-d6): δ = 7.98 (d, J = 4.0 Hz, 1H), 7.67 (dd, J = 8.0, 1.0 Hz, 1H), 7.54 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 (dd, J = 7.6, 1.0 Hz, 1H), 7.29 (dd, J = 7.7, 1.7 Hz, 1H), 4.56 - 4.51 (m, 1H), 3.51 (dd, J = 17.3, 12.1 Hz, 1H), 3.24 (ddd, J = 17.3, 9.0, 1.4 Hz, 1H) ppm.

[0223] 13 C NMR (151 MHz, DMSO-d6): δ = 149.1, 133.9, 133.2, 130.8, 130.4, 127.8, 125.9 (q, J C-F = 279.8 Hz), 120.5, 59.6 (q, J C-F = 29.3 Hz), 35.74 ppm.

[0224] 19 F NMR (376 MHz, DMSO-d6): δ = -74.72 (d, J C-F = 7.5 Hz, 3F) ppm.

[0225] HRMS (ESI): calcd for C10 H9N2BrF3[M+H] + :292.9739,found 292.97346.

[0226] Example 30:

[0227] 1 H NMR (600MHz, DMSO-d6): δ = 8.02 (s, 1H), 7.95–7.93 (m, 3H), 7.89 (t, J = 6.9Hz, 2H), 7.55–7.50 (m,2H),4.61–4.54(m,1H),3.58(dd,J=17.1,12.2Hz,1H),3.24(dd,J=17.1,9.0Hz,1H)ppm.

[0228] 13 C NMR (101MHz, DMSO-d6): δ = 149.8, 133.1, 133.0, 129.7, 128.3, 128.1, 127.7, 126.7, 126.6, 126.1 (q, J C-F =279.8Hz),125.7,123.1,59.4(q,J C-F =29.3Hz), 33.3ppm.

[0229] 19 F NMR (376MHz, DMSO-d6): δ = -74.65 (d, J C-F =7.5Hz, 3F)ppm.

[0230] HRMS(ESI):calcd for C 14 H 12 N2F3[M+H] + :265.0790,found 265.0787.

[0231] Example 31:

[0232] 1 H NMR (400MHz, DMSO-d6): δ = 8.68 (s, 1H), 8.15–8.13 (m, 2H), 8.06–8.05 (m, 1H), 7.93–7.91 (m,2H),7.59–7.55(m,4H),4.91–4.79(m,1H),3.62–3.54(m,1H),3.22–3.15(m,1H)ppm.

[0233] 13C NMR (151 MHz, DMSO-d6): δ = 149.4, 131.0, 129.6, 128.8, 128.0, 127.1, 126.8, 126.2 (q, J = 278.6 Hz), 125.7, 125.0, 59.1 (q, J = 29.4 Hz) ppm. C-F C-F = 278.6 Hz), 125.7, 125.0, 59.1 (q, J = 29.4 Hz) ppm.

[0234] 19 F NMR (376 MHz, DMSO-d6): δ = -74.61 (d, J = 7.6 Hz, 3F) ppm.

[0235] HRMS (ESI): calcd for C 18 H 14 N2F3[M + H] + : 315.1152, found 315.1146.

[0236] Example 32:

[0237] 1 H NMR (400 MHz, DMSO-d6): δ = 8.04 (d, J = 4.3 Hz, 1H), 7.93 - 7.90 (m, 1H), 7.82 - 7.80 (m, 1H), 7.53 (s, 1H), 7.38 - 7.35 (m, 2H), 4.68 - 4.56 (m, 1H), 3.55 (dd, J = 17.1, 12.2 Hz, 1H), 3.22 (dd, J = 16.9, 8.7 Hz, 1H) ppm.

[0238] 13 C NMR (151 MHz, DMSO-d6): δ = 146.0, 139.6, 139.1, 135.6, 126.2 (q, J = 277.8 Hz), 125.6, 124.9, 124.1, 124.0, 122.6, 59.8 (q, J = 28.7 Hz), 33.7 ppm. C-F C-F = 277.8 Hz), 125.6, 124.9, 124.1, 124.0, 122.6, 59.8 (q, J = 28.7 Hz), 33.7 ppm.

[0239] 19 F NMR (376 MHz, DMSO-d6): δ = -74.73 (d, J = 7.5 Hz, 3F) ppm. C-F 12 = 277.8 Hz), 125.6, 124.9, 124.1, 124.0, 122.6, 59.8 (q, J = 28.7 Hz), 33.7 ppm.

[0240] HRMS (ESI): calcd for C 10 H + N2F3S[M + H] : 315.1152, found 315.1146.​​271.0511, found 271.0509.

[0241] Example 33:

[0242] 1 H NMR (400 MHz, DMSO-d6): δ = 8.59 (dd, J = 4.5, 1.6 Hz, 2H), 8.29 (d, J = 3.4 Hz, 1H), 7.55 (dd, J = 4.5, 1.6 Hz, 2H), 4.68 - 4.56 (m, 1H), 3.46 (dd, J = 17.5, 12.5 Hz, 1H), 3.14 (dd, J = 17.5, 9.0, 1H) ppm.

[0243] 13 C NMR (151 MHz, DMSO-d6): δ = 150.1, 150.0, 147.2, 139.2, 139.1, 125.8 (q, J C-F = 279.4 Hz), 119.9, 59.7 (q, J C-F = 30.2 Hz), 32.4 ppm.

[0244] 19 F NMR (376 MHz, DMSO-d6): δ = -74.90 (d, J C-F = 7.5 Hz, 3F) ppm.

[0245] HRMS (ESI): calcd for C9H9N3F3 [M+H] + : 216.0586, found 216.0583.

[0246] Example 34:

[0247] 1 H NMR (400 MHz, DMSO-d6): δ = 7.72 (d, J = 4.6 Hz, 1H), 7.51 - 7.49 (m, 2H), 6.94 - 6.90 (m, 3H), 6.73 (d, J = 16.4 Hz, 1H), 4.50 - 4.40 (m, 1H), 3.77 (s, 3H), 3.28 (dd, J = 16.9, 12.1 Hz, 1H), 2.92 (dd, J = 16.9, 8.7 Hz, 1H) ppm.

[0248] 13 C NMR (101 MHz, DMSO-d6): δ = 159.5, 151.2, 133.3, 129.1, 128.2, 126.0 (q, J C-F= 279.8 Hz), 118.8, 114.3, 59.0 (q, J = 279.8 Hz), 55.2, 32.3 ppm. C-F = 29.3 Hz), 55.2, 32.3 ppm.

[0249] 19 F NMR (376 MHz, DMSO-de): δ = -74.81 (d, J = 279.8 Hz), 122.28, 121.51, 59.8 (q, J = 279.8 Hz), 55.2, 32.3 ppm. C-F = 7.5 Hz, 3F) ppm.

[0250] HRMS (ESI): calcd for C 13 H 14 ON2F3 [M+H] + : 271.1052, found 271.1051.

[0251] Example 35:

[0252] 1 H NMR (400 MHz, DMSO-de): δ = 7.91 (d, J = 4.3 Hz, 1H), 7.54 - 7.49 (m, 4H), 7.09 (d, J = 16.4 Hz, 1H), 6.74 (d, J = 16.4 Hz, 1H), 4.54 - 4.44 (m, 1H), 3.29 (dd, J = 17.0, 12.2 Hz, 1H), 2.94 (dd, J = 17.0, 8.7 Hz, 1H) ppm.

[0253] 13 C NMR (101 MHz, DMSO-de): δ = 150.95, 136.13, 132.37, 132.08, 129.02, 126.2 (q, J = 29.3 Hz), 32.45 ppm. C-F = 279.8 Hz), 122.28, 121.51, 59.8 (q, J = 279.8 Hz), 55.2, 32.3 ppm. C-F = 29.3 Hz), 55.2, 32.3 ppm.

[0254] 19 F NMR (376 MHz, DMSO-de): δ = -74.93 (d, J = 279.8 Hz), 122.28, 121.51, 59.8 (q, J = 279.8 Hz), 55.2, 32.3 ppm. C-F = 7.5 Hz, 3F) ppm.

[0255] HRMS (ESI): calcd for C 12 H 10 N2BrF3 [M+H] + : 319.0052, found 319.0051.

[0256] Example 36:

[0257] 1 1H NMR (400 MHz, DMSO-d6): δ = 8.01 (d, J = 4.2 Hz, 1H), 7.88 (dd, J = 8.8, 6.2 Hz, 1H), 7.60 (dd, J = 8.5, 2.6 Hz, 1H), 7.26 (dd, J = 8.6, 2.6 Hz, 1H), 7.06 (d, J = 16.3 Hz, 1H), 6.82 (d, J = 16.3 Hz, 1H), 4.54–4.45 (m, 1H), 3.35–3.28 (m, 1H), 2.93 (dd, J = 16.8, 8.8 Hz, 1H) ppm.

[0258] 13 13C NMR (151 MHz, DMSO-d6): δ = 162.2, 160.6, 150.1, 132.5 (d, J C-F = 4.5 Hz), 129.5, 128.6 (d, J C-F = 9.0 Hz), 126.1 (q, J C-F = 279.8 Hz), 124.2 (d, J C-F = 1.5 Hz), 123.3 (d, J C-F = 9.0 Hz), 120.10 (d, J​​​​​​​​​​​​​​​​​​​​​​​​​​​​​H NMR (400 MHz, DMSO-d6): δ = 7.85 - 7.84 (m, 1H), 7.19 (s, 1H), 6.92 (s, 1H), 6.59 - 6.56 (d, J = 12.0 Hz, 1H), 6.46 - 6.43 (d, J = 12.0 Hz, 1H), 4.38 - 4.26 (m, 1H), 3.79 - 3.75 (m, 6H), 2.62 - 2.55 (m, 1H), 2.38 - 2.32 (m, 1H) ppm.

[0263] 13 C NMR (101 MHz, DMSO-d6): δ = 149.2, 148.3, 147.7, 131.1, 129.1, 125.7 (q, J = 278.8 Hz), 124.0, 115.0, 114.0, 113.3, 59.5 (q, J = 29.3 Hz), 56.0, 55.8, 34.0 ppm.

[0264] 19 F NMR (376 MHz, DMSO-d6): δ = -75.24 (d, J = 7.4 Hz, 3F) ppm.

[0265] HRMS (ESI): calcd for C 14 H 15 O2N2BrF3[M+H] + : 379.0230, found 379.0225.

[0266] E configuration in Example 37:

[0267] 1 H NMR (400 MHz, DMSO-d6): δ = 7.90 - 7.89 (m, 1H), 7.31 (s, 1H), 7.14 - 7.08 (m, 2H), 6.79 (d, J = 16.0 Hz, 1H), 4.53 - 4.41 (m, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.32 - 3.27 (m, 1H), 2.95 - 2.89 (m, 1H) ppm.

[0268] 13 C NMR (101 MHz, DMSO-d6): δ = 150.6, 149.8, 148.7, 130.7, 127.7, 125.9 (q, J = 278.3 Hz), 122.3, 115.5, 114.2, 109.2, 59.2 (q, J = 29.5 Hz), 56.0, 55.9, 32.0 ppm.

[0269] 19 F NMR (376 MHz, DMSO-d6): d = -74.82 (d, J = 7.3 Hz, 3F) ppm.

[0270] HRMS (ESI): calcd for C 14 H 15 O2N2BrF3[M+H] + : 379.0230, found 379.0225.

[0271] Example 38:

[0272] 1 H NMR (400 MHz, DMSO-d6): d = 8.41 - 8.39 (m, 1H), 7.91 - 7.85 (m, 4H), 7.59 - 7.55 (m, 4H), 7.13 (d, J = 16.1 Hz, 1H), 4.57 - 4.47 (m, 1H), 3.48 (dd, J = 17.2, 12.2 Hz, 1H), 3.18 (dd, J = 17.2, 8.9 Hz, 1H) ppm.

[0273] 13 C NMR (151 MHz, DMSO-d6): d = 151.7, 133.9, 133.8, 131.0, 130.1, 128.9, 128.8, 126.4 (q, J = 279.8 Hz), 124.2, 124.0, 123.8, 59.60 (q, J = 28.7 Hz), 32.68. C-F = 279.8 Hz), 124.2, 124.0, 123.8, 59.60 (q, J = 28.7 Hz), 32.68. C-F = 279.8 Hz), 124.2, 124.0, 123.8, 59.60 (q, J = 28.7 Hz), 32.68.

[0274] 19 F NMR (376 MHz, DMSO-d6): d = -74.68 (d, J = 7.5 Hz, 3F) ppm. C-F F NMR (376 MHz, DMSO-d6): d = -74.68 (d, J = 7.5 Hz, 3F) ppm.

[0275] Example 39:

[0276] 1 H NMR (400 MHz, DMSO-d6): d = 7.98 (s, 1H), 7.92 - 7.86 (m, 4H), 7.81 - 7.78 (m, 1H), 7.50 - 7.47 (m, 2H), 7.22 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 16.0 Hz, 1H), 4.55 - 4.47 (m, 1H), 3.38 - 3.31 (m, 1H), 3.04 - 3.01 (m, 1H) ppm.

[0277] 13C NMR (101 MHz, DMSO-d6): δ = 150.9, 134.1, 133.4, 133.3, 132.9, 128.4, 128.1, 127.7, 126.9, 126.6, 126.4, 126.0 (q, J = 278.5 Hz), 123.7, 121.6, 59.2 (q, J = 29.5 Hz), 32.2 ppm.

[0278] 19 F NMR (376 MHz, DMSO-d6): δ = -74.81 (d, J = 7.6 Hz, 3F) ppm.

[0279] HRMS (ESI): calcd for C 16 H 14 N2F3[M+H] + : 291.1207, found 291.1199.

[0280] Example 40:

[0281] 1 H NMR (400 MHz, DMSO-d6): δ = 8.53 (dd, J = 6.1, 1.3 Hz, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 6.1 Hz, 2H), 7.34 (d, J = 16.5 Hz, 1H), 6.74 (d, J = 16.5 Hz, 1H), 4.59 - 4.50 (m, 1H), 3.40 - 3.27 (m, 1H), 2.96 (dd, J = 17.1, 8.6 Hz, 1H) ppm.

[0282] 13 C NMR (151 MHz, DMSO-d6): δ = 150.1, 150.0, 143.8, 130.5, 125.8 (q, J C-F = 279.4 Hz), 125.5, 121.1, 59.4 (q, J C-F = 30.2 Hz), 31.9 ppm.

[0283] 19 F NMR (376 MHz, DMSO-d6): δ = -74.68 (d, J C-F = 7.5 Hz, 3F) ppm.

[0284] HRMS (ESI): calcd for C 11 H 11 N3F3[M+H] + : 242.0899, found 242.0897.

[0285] Example 41:

[0286] 1 H NMR (400 MHz, DMSO-d6): δ = 7.55 (d, J = 5.5 Hz, 1H), 7.32 (dd, J = 7.8, 1.6 Hz, 2H), 7.24 - 7.22 (m, 3H), 6.29 (d, J = 15.9 Hz, 1H), 6.06 (dt, J = 15.9, 6.9 Hz, 1H), 4.40 - 4.31 (m, 1H), 3.50 (d, J = 6.9 Hz, 2H), 3.15 (dd, J = 17.2, 12.1 Hz, 1H), 2.78 (dd, J = 17.1, 8.8 Hz, 1H) ppm.

[0287] 13 C NMR (151 MHz, DMSO-d6): δ = 150.8, 139.6, 135.6, 128.7, 128.6, 126.3, 126.0 (q, J C-F = 279.3 Hz), 123.9, 58.8 (q, J C-F = 28.7 Hz), 38.5, 32.4 ppm.

[0288] 19 F NMR (376 MHz, DMSO-d6): δ = -74.77 (d, J C-F = 7.5 Hz, 3F) ppm.

[0289] HRMS (ESI): calcd for C 13 H 14 N2F3 [M+H] + : 255.1143, found 255.1138.

[0290] Example 42:

[0291] 1 H NMR (400 MHz, DMSO-d6): δ = 7.78 (s, 2H), 7.77 (s, 1H), 7.45 - 7.34 (m, 4H), 7.34 (d, J = 3.7 Hz, 1H), 4.71 - 4.59 (m, 1H), 3.48 - 3.41 (m, 1H), 3.15 (dd, J = 17.0, 8.9 Hz, 1H) ppm.

[0292] 13C NMR (151 MHz, DMSO-d6): δ = 148.9, 135.3, 132.6, 129.6, 128.7, 128.4, 125.8 (q, J = 279.4 Hz), 115.2, 60.8 (q, J = 30.2 Hz), 33.2 ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -74.93 (d, J = 7.5 Hz, 3F) ppm. C-F HRMS (ESI): calcd for C 19 H C-F N2F3 [M+H] : 238.0782, found 238.0791.

[0293] 12 F NMR (376 MHz, DMSO-d6): δ = -74.93 (d, J = 7.5 Hz, 3F) ppm. 11 HRMS (ESI): calcd for C + H

[0294] N2BrF3 [M+H] : 319.0052, found 319.0051.

[0295] Example 43:

[0296] 1 H NMR (400 MHz, DMSO-d6): δ = 8.22 (d, J = 3.2 Hz, 1H), 7.54 - 7.51 (m, 2H), 7.45 - 7.43 (m, 3H), 4.60 - 4.50 (m, 1H), 3.25 (dd, J = 17.4, 12.5 Hz, 1H), 2.93 (dd, J = 17.4, 8.8 Hz, 1H) ppm.

[0297] 13 C NMR (151 MHz, DMSO-d6): δ = 133.1, 131.5, 129.5, 129.0, 125.5 (q, J = 279.4 Hz), 121.4, 92.7, 82.7, 59.4 (q, J = 30.2 Hz), 36.2 ppm. C-F F NMR (376 MHz, DMSO-d6): δ = -75.15 (d, J = 7.5 Hz, 3F) ppm. C-F HRMS (ESI): calcd for C 19 H C-F N2F3 [M+H] : 238.0782, found 238.0791.

[0298] 12 F NMR (376 MHz, DMSO-d6): δ = -74.93 (d, J = 7.5 Hz, 3F) ppm. 10 HRMS (ESI): calcd for C + H

[0299] N2BrF3 [M+H] : 319.0052, found 319.0051.

[0300] Example 44:

[0301] 1 H NMR (400 MHz, DMSO-d6): δ = 9.66 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.44 (s, 1H), 7.39 (t, J = 7.1 Hz, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 4.91 - 4.84 (m, 1H), 4.80 (d, J = 8.3 Hz, 1H) ppm.

[0302] 13 C NMR (101 MHz, DMSO-d6): δ = 136.9, 129.5, 128.7, 127.9, 124.6 (q, J = 280.8 Hz), 123.8, 114.3, 68.1 (q, J = 30.3 Hz), 51.3, 51.2 ppm. C-F C-F F NMR (376 MHz, DMSO-d6): δ = -75.29 (s, 3F) ppm.

[0303] 19 HRMS (ESI): calcd for C 11 H9N3F3 [M+H]: 240.0743, found 240.0741.

[0304] HRMS (ESI): calcd for C + H9N3F3 [M+H]: 240.0743, found 240.0741.

[0305] Example 45:

[0306] 1 H NMR (400 MHz, DMSO-d6): δ = 9.17 (s, 1H), 7.10 - 7.06 (m, 2H), 6.93 - 6.90 (m, 2H), 4.52 - 4.48 (m, 1H), 4.38 (d, J = 6.2 Hz, 1H), 4.10 - 3.98 (m, 2H), 3.73 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H) ppm.

[0307] 13 C NMR (151 MHz, DMSO-d6): δ = 161.1, 158.8, 141.6, 131.5, 128.5, 125.0 (q, J = 280.6 Hz), 114.4, 68.5 (q, J = 29.2 Hz), 60.4, 55.2, 49.7, 14.0 ppm.

[0308] 19 ​F NMR (376 MHz, DMSO-d6): d = -76.36 (d, J = 7.7 Hz, 3F) ppm.

[0309] HRMS (ESI): calcd for C 14 H 16 O3N2F3[M+H] + : 317.1107, found 317.1103.

[0310] Example 46:

[0311] 1 H NMR (400 MHz, DMSO-d6): d = 9.78 (s, 1H), 7.98 - 7.96 (m, 2H), 7.59 - 7.57 (m, 1H), 7.50 - 7.46 (m, 2H), 7.38 - 7.34 (m, 2H), 7.30 - 7.23 (m, 3H), 4.74 - 4.65 (m, 2H) ppm.

[0312] 13 C NMR (151 MHz, DMSO-d6): d = 185.8, 148.5, 139.6, 137.0, 132.6, 129.5, 129.1, 128.3, 127.7, 127.4, 124.9 (q, J = 275.57 Hz), 68.0 (q, J = 29.5 Hz), 50.0 ppm.

[0313] 19 F NMR (376 MHz, DMSO-d6): d = -76.25 (d, J = 7.2 Hz, 3F) ppm.

[0314] HRMS (ESI): calcd for C 17 H 14 ON2F3[M+H] + : 319.1052, found 319.1048.

[0315] Example 47:

[0316] 11H NMR (400 MHz, DMSO-d6): δ = 7.79 (d, J = 3.2 Hz, 1H), 7.67 (t, J = 1.8 Hz, 1H), 7.66 (q, J = 1.9 Hz, 1H), 7.41–7.40 (m, 1H), 7.37 (t, J = 1.8 Hz, 1H), 7.36–7.32 (m, 1H), 4.15–4.07 (m, 1H), 3.76–3.69 (m, 1H), 1.24 (d, J = 7.1 Hz, 3H) ppm. 1 122> 13 13C NMR (151 MHz, DMSO-d6): δ = 141.8, 129.2, 128.8 (q, J = 268.8 Hz), 128.7, 127.8, 126.2, 110.9, 48.8, 18.1, 8.1 ppm.

[0318] 19 19F NMR (376 MHz, DMSO-d6): δ = -75.79 (d, J C-F = 7.5 Hz, 3F) ppm.

[0319] HRMS (ESI): calcd for C 11 H 12 N2F3 [M + H] + : 229.0976, found 229.0969.

[0320] Example 48:

[0321] <( 1 1H NMR (400 MHz, DMSO-d6): δ = 9.93 (s, 1H), 5.25–5.17 (m, 1H), 4.57–4.49 (m, 1H), 4.27–4.19 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H) ppm.

[0322] 13 13C NMR (151 MHz, DMSO-d6): δ = 160.6, 131.0, 124.3 (q, J = 279.9 Hz), 123.7 (q, J = <281.2 Hz), 61.4 (q, J = 32.5 Hz), 60.9, 48.3 (q, J = 30.5 Hz), 14.1 ppm.

[0323] 19 19F NMR (376 MHz, DMSO-d6): δ = -68.73 (d, J = 8.6 Hz, 3F), -77.13 (d, J = 7.6 Hz, 3F) ppm.

[0324] HRMS (ESI): calcd for C8H9N2F6 [M+H] + : 279.0550, found 279.0541.

[0325] Example 49:

[0326] 1 H NMR (400 MHz, DMSO-d6): δ = 9.02 (s, 1H), 4.35-4.27 (m, 1H), 4.23-4.11 (m, 2H), 3.29-3.27 (m, 1H), 1.26-1.21 (m, 6H) ppm.

[0327] 13 C NMR (151 MHz, DMSO-d6): δ = 161.50, 142.45, 125.12 (q, J = 280.1 Hz), 66.68 (q, J = 29.3 Hz), 60.40, 17.62, 14.19 ppm.

[0328] 19 F NMR (376 MHz, DMSO-d6): δ = -76.14 (d, J = 7.7 Hz, 3F) ppm.

[0329] HRMS (ESI): calcd for C8H 12 O2N2F3 [M+H] + : 225.0845, found 225.0845.

[0330] Examples 50-59

[0331] Different from Example 17, different vinyl monomers were used, and different reaction time was used to prepare the corresponding product, and the rest of the material usage and reaction temperature were the same as Example 17, and the specific operation was shown in Table 3.

[0332] Table 3

[0333]

[0334]

[0335] As can be seen, when aliphatic alkenes are reacted instead of aromatic and internal alkenes, the corresponding isomer 3-trifluoromethylpyrazoline is obtained chemoselectively. Acetic acid alkenes with aryl, aryl (thio) ether, or diethyl malonate alkyl chain ends successfully yielded the target product (the products of Examples 50-53) in moderate to good yields. Similarly, alkyl-terminated alkenes with more aliphatic chains (such as bulky cyclohexyl and n-pentyl) are also suitable substrates, with 3-trifluoromethylpyrazoline (the products of Examples 54-55) yielding up to 75%. Notably, an efficient cycloaddition reaction was carried out on electron-rich vinylamides to give 3-trifluoromethylpyrazoline (the product of Example 56) in a yield of 60%, which not only expands the olefin dipoleophile molecule to an electron-rich electrophile but also provides a novel 5-amino-substituted 3-trifluoromethylpyrazoline scaffold. Furthermore, diallyl sulfonate exhibits good reactivity, yielding the corresponding bispyrazoline (the product of Example 57) in a 91% yield. Finally, the 1,1-disubstituted olefins were all compatible, resulting in 3-trifluoromethylpyrazoline having a quaternary ammonium salt in a moderate yield (Examples 58-59).

[0336] The structural characterization data of the products from Examples 50-59 are as follows:

[0337] Example 50:

[0338] 1 H NMR (400MHz, DMSO-d6): δ = 7.89 (s, 1H), 7.32–7.28 (m, 2H), 7.24–7.19 (m, 3H), 4.16 (dt, J = 16.7, 8.3Hz, 1H), 2. 85(dd,J=13.6,5.1Hz,1H),2.79(dd,J=10.4,6.3Hz,1H),2.71(dd,J=13.5,7.8Hz,1H),2.57–2.50(m,1H)ppm.

[0339] 13 C NMR (101MHz, DMSO-d6): δ=137.7,136.9(q,J C-F =36.4Hz),129.3,128.7,128.6,128.5,126.5,121.6(q,J C-F =268.7Hz), 62.4, 34.0ppm.

[0340] 19 F NMR (376MHz, DMSO-d6): δ = -65.06 (d, J C-F =22.56Hz, 3F)ppm.

[0341] HRMS (ESI): calcd for C 11 H 12 N2F3[M+H] + : 229.0947, found 229.0945.

[0342] Example 51:

[0343] 1 H NMR (400 MHz, DMSO-d6): δ = 8.09 (s, 1H), 7.31 - 7.27 (m, 2H), 6.96 (dd, J = 7.5, 0.8 Hz, 2H), 6.93 (s, 1H), 4.30 - 4.27 (m, 1H), 3.99 (dd, J = 9.9, 5.0 Hz, 1H), 3.95 (dd, J = 9.8, 6.2 Hz, 1H), 3.04 - 3.01 (m, 1H), 2.75 (dd, J = 16.9, 8.7 Hz, 1H) ppm.

[0344] 13 C NMR (101 MHz, DMSO-d6): δ = 158.4, 137.4 (q, J C-F = 36.4 Hz), 129.6, 121.5 (q, J C-F = 269.7 Hz), 121.0, 114.6, 69.1, 59.9, 32.2 ppm.

[0345] 19 F NMR (376 MHz, DMSO-d6): δ = -65.00 (s, 3F) ppm.

[0346] HRMS (ESI): calcd for C 11 H 12 ON2F3[M+H] + : 245.0896, found 245.0895.

[0347] Example 52:

[0348] 11H NMR (400 MHz, DMSO-d6): δ = 7.98 (s, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.35–7.31 (m, 2H), 7.24–7.20 (m, 1H), 4.05–4.04 (m, 1H), 3.14 (dd, J = 13.5, 5.4 Hz, 1H), 3.05 (dd, J = 13.5, 7.4 Hz, 1H), 3.02–2.94 (m, 1H), 2.69 (dd, J = 17.0, 8.5 Hz, 1H) ppm.

[0349] 13 13C NMR (101 MHz, DMSO-d6): δ = 137.3 (q, J C-F = 36.4 Hz), 135.4, 129.3, 128.8, 126.2, 121.4 (q, J C-F = 269.7 Hz), 60.2, 36.0, 34.3 ppm.

[0350] 19 19F NMR (376 MHz, DMSO-d6): δ = -64.94 (s, 3F) ppm.

[0351] HRMS (ESI): calcd for C 11 H 12 N2F3S [M + H] + [[ID=二十一]]: 261.0667, found 261.06675.

[0352] Example 53:

[0353] 1 1H NMR (400 MHz, DMSO-d6): δ = 7.97 (s, 1H), 4.20–4.10 (m, 4H), 3.92–3.8 (m, 形, 1H), 3.65 (t, J = 7.4 Hz, 1H), 2.96–2.89 (m, 1H), 2.58 (dd, J = 16.8, 9.5 Hz, 1H), 2.02–1.98 (m, 2H), 1.21–1.17 (m, 6H).

[0354] 13 13C NMR (101 MHz, DMSO-d6): δ = 169.2, 169.1, 138.9 (q, J C-F = 36.2 Hz), 121.8 (q, J C-F= 269.8 Hz), 61.61, 61.55, 59.44, 48.54, 40.18, 40.04, 39.91, 39.77, 39.63, 34.78, 33.02, 14.25 ppm.

[0355] 19 F NMR (376 MHz, DMSO-d6): δ = -65.22 (s, 3F) ppm.

[0356] HRMS (ESI): calcd for C 12 H 18 O4N2F3[M+H] + : 311.1277, found 311.1273.

[0357] Example 54:

[0358] 1 H NMR (400 MHz, DMSO-d6): δ = 7.93 (s, 1H), 3.86 - 3.81 (m, 1H), 2.91 (dd, J = 16.4, 11.0 Hz, 1H), 2.44 (dd, J = 16.4, 10.1 Hz, 1H), 1.51 - 1.38 (m, 2H), 1.32 - 1.30 (m, 6H), 0.88 - 0.84 (m, 3H) ppm.

[0359] 13 C NMR (151 MHz, DMSO-d6): δ = 137.0 (q, J C-F = 36.2 Hz), 121.7 (q, J C-F = 268.8 Hz), 61.6, 34.6, 34.1, 31.3, 25.2, 22.2, 14.0 ppm.

[0360] 19 F NMR (376 MHz, DMSO-d6): δ = -64.93 (s, 3F) ppm.

[0361] HRMS (ESI): calcd for C9H 16 N2F3[M+H] + : 209.1286, found 209.1280.

[0362] Example 55:

[0363] 1H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 1 H), 4.00 - 3.91 (m, 1 H), 2.98 - 2.91 (m, 1 H), 2.46 - 2.38 (m, 1 H), 1.73 - 1.60 (m, 5H), 1.46 - 1.11 (m, 6H), 0.92 - 0.83 (m, 2H) ppm.

[0364] 13 C NMR (151 MHz, DMSO-d6): δ = 137.2 (q, J C-F = 34.7 Hz), 121.7 (q, J C-F = 268.8 Hz), 59.3, 42.0, 35.2, 34.3, 33.1, 32.7, 26.2, 25.9, 25.8 ppm.

[0365] 19 F NMR (376 MHz, DMSO-d6): δ = -64.84 (s, 3F) ppm.

[0366] HRMS (ESI): calcd for C 11 H 18 N2F3 [M+H] + : 235.1456, found 235.1450.

[0367] Example 56:

[0368] 1 H NMR (400 MHz, DMSO-d6): δ = 8.23 (s, 1 H), 5.87 (dd, J = 10.4, 2.2 Hz, 1 H), 3.16 - 3.04 (m, 2H), 2.95 - 2.80 (m, 2H), 2.27 - 2.13 (m, 2H), 1.93 - 1.85 (m, 2H) ppm.

[0369] 13 C NMR (101 MHz, DMSO-d6): δ = 174.0, 135.9 (q, J C-F = 36.4 Hz), 121.3 (q, J C-F = 268.7 Hz), 66.3, 41.1, 32.5, 30.6, 17.4 ppm.

[0370] 19 F NMR (376 MHz, DMSO-d6): δ = -64.36 (s, 3F) ppm.

[0371] HRMS (ESI): calcd for C8H11 N3F3[M+H] + : 222.0743, found 222.0741.

[0372] Example 57:

[0373] 1 H NMR (400 MHz, DMSO-d6): δ = 7.92 (s, 2H), 4.12 - 4.04 (m, 2H), 3.01 - 2.94 (m, 2H), 2.73 - 2.70 (m, 2H), 2.67 (dd, J = 11.8, 4.7 Hz, 4H) ppm.

[0374] 13 C NMR (101 MHz, DMSO-d6): δ = 137.3 (q, J = 36.4 Hz), 121.5 (q, J = 269.7 Hz), 60.8, 35.1, 34.3 ppm. C-F C-F = 269.7 Hz), 60.8, 35.1, 34.3 ppm.

[0375] 19 F NMR (376 MHz, DMSO-d6): δ = -64.99 (s, 3F), -65.06 (s, 3F) ppm.

[0376] HRMS (ESI): calcd for C 10 H 13 N4F6S [M+H] + : 335.0759, found 335.0757.

[0377] Example 58:

[0378] 1 H NMR (400 MHz, DMSO-d6): δ = 8.45 (s, 1H), 7.42 - 7.39 (m, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.1 Hz, 1H), 3.10 (dd, J = 16.7, 1.2 Hz, 1H), 2.92 (dd, J = 16.7, 2.0 Hz, 1H), 1.45 (s, 3H) ppm.

[0379] 13 C NMR (151 MHz, DMSO-d6): δ = 145.9, 135.8 (q, J = 36.2 Hz), 128.6, 127.2, 125.6, 121.6 (q, J = 268.8 Hz), 70.1, 43.5, 27.4 ppm. C-F C-F = 268.8 Hz), 70.1, 43.5, 27.4 ppm. ​​

[0380] 19 F NMR (376 MHz, DMSO-d6): d = -64.73 (s, 3F) ppm.

[0381] HRMS (ESI): calcd for C 11 H 12 N2F3[M+H] + : 229.0895, found 229.0889.

[0382] Example 59:

[0383] 1 H NMR (400 MHz, DMSO-d6): d = 8.42 (s, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.1 Hz, 1H), 3.17 (d, J = 17.0 Hz, 1H), 3.05 (d, J = 17.0 Hz, 1H), 1.31 - 1.23 (m, 1H), 0.47 - 0.43 (m, 1H), 0.36 (d, J = 6.1 Hz, 1H), 0.33 - 0.31 (m, 1H), 0.20 (dt, J = 14.8, 5.5 Hz, 1H) ppm.

[0384] 13 C NMR (151 MHz, DMSO-d6): d = 145.2, 134.9 (q, J C-F = 36.2 Hz), 128.4, 127.1, 126.0, 121.6 (q, J C-F = 267.3 Hz), 72.5, 42.1, 20.4, 1.7, 1.0 ppm.

[0385] 19 F NMR (376 MHz, DMSO-d6): d = -64.70 (s, 3F) ppm.

[0386] HRMS (ESI): calcd for C 13 H 14 N2F3[M+H] + : 255.1156, found 255.1150.

[0387] Examples 60-67

[0388] Unlike example 17, different ethylene monomers were used, different reaction times were used to prepare the corresponding products, the rest of the material amount and reaction temperature were the same as example 17, and the specific operation was shown in table 4.

[0389] Table 4

[0390]

[0391]

[0392] As shown in examples 60-67, the present application carried out derivatization reaction on various olefin scaffolds of natural products and bioactive heterocycles, and the olefin from the clinical drug artemisinin for treating malaria was used to provide the desired product (the product of example 60) under the reaction conditions described in the present application with a yield of 69%, and the present application also studied several olefins from natural products such as cholesterol, protected oleanolic acid and flavonoids, and directly synthesized the corresponding trifluoromethyl pyrazoline containing products (examples 61-63) using this cycloaddition strategy, with high yield. In addition, furanose derived olefins and other olefins derived from indole, acridone and dihydroazepine are all suitable for the reaction, and the corresponding trifluoromethyl pyrazoline products are constructed with excellent yield (examples 64-67). However, two regioisomers were observed for the products of examples 63-66 under the reaction conditions, the main reason is the electrophilic and steric hindrance effect produced by the functionalized scaffold (the product of examples 63-66), which provides extensive possibilities for further structural development.

[0393] The product structure characterization data of examples 60-67 are as follows:

[0394] Example 60:

[0395] 1 H NMR (400 MHz, DMSO-d6): δ = 7.88 (s, 1H), 5.40 (s, 1H), 4.70-4.68 (m, 1H), 4.13-4.09 (m, 1H), 3.76-3.73 (m, 1H), 3.32-3.28 (m, 2H), 3.27-3.26 (m, 1H), 2.99-2.92 (m, 1H), 2.73-2.67 (m, 1H), 2.39-2.38 (m, 1H), 2.18 (td, J = 14.0, 3.9 Hz, 1H), 2.01-1.96 (m, 1H), 1.83-1.78 (m, 1H), 1.68-1.47 (m, 3H), 1.41-1.28 (m, 5H), 1.15-1.10 (m, 1H), 0.88 (d, J = 3.5 Hz, 3H), 0.82 (d, J = 3.5 Hz, 3H) ppm.

[0396] 13 C NMR (151MHz, DMSO-d6): δ = 136.4 (q, J C-F =36.2Hz), 136.2(q,J C-F =36.2Hz), 121.7(q,J C-F =268.8Hz), 121.6(q,J C-F =268.8Hz),103.5,103.4,101.5,100.8,87.1,87.0,80.7,80.6,69.9,69.4,59.9,59.8,52.2,52.1,43.9,36.5,36 .4,36.2,36.1,34.3,34.3,32.3,31.8,30.6,30.6,25.8,25.8,24.5,24.4,24.0,23.8,20.3,20.3,12.7,12.6ppm.

[0397] 19 F NMR (376MHz, DMSO-d6): δ = -64.97 (s, 3F), -76.30 (d, J = 7.2Hz, 3F) ppm.

[0398] HRMS(ESI):calcd for C 20 H 30 O5N2F3[M+H] + :435.2157,found 435.2147.

[0399] Example 61:

[0400] 1H NMR(400MHz,CDCl3):δ=6.18(s,1H),5.34(d,J=3.9Hz,1H),4.14–4.06(m,1H),3.42(dd,J=9.2,4.7Hz,1H),3.39–3.35(m,1H),3.19–3.11(m,1H),2.93(ddd,J=16.8,10.7,1.5Hz,1H),2.54(dd,J=16.9,6.5Hz,1H),2.32(dd,J=13.1,3.4Hz,1H),2.21–2.14(m,1H),2.02–1.95(m,2H),1.87(s,1H),1.84–1.78(m,2H),1.60–1.55(m,1H),1.50(ddd,J=24.6,12.0,5.5Hz,5H),1.43(d,J=3.9Hz,1H),1.41–1.33(m,2H),1.31–1.17(m,3H),1.16–1.11(m,3H),1.09–1.04(m,2H),1.03(d,J=12.7Hz,2H),0.99(s,4H),0.92(s,2H),0.90(s,2H),0.87(d,J=1.7Hz,3H),0.85(d,J=1.7Hz,3H),0.67(s,3H)ppm。

[0401] 13 C NMR(151MHz,CDCl3):δ=141.2(q,J C-F =37.8Hz),140.5,122.0,120.7(q,J C-F =268.8Hz),79.79,69.03,60.58,56.73,56.12,50.11,42.30,39.73,39.50,38.96,37.08,37.07,36.83,36.17,35.79,32.55,31.92,28.23,28.02,24.28,23.82,22.83,22.57,21.05,19.36,18.71,11.85ppm。

[0402] 19 F NMR(376MHz,CDCl3):δ=-67.09(s,3F)ppm。

[0403] HRMS(ESI):calcd for C 32 H 52 ON2F3[M+H] + :537.4026,found 537.4024.

[0404] Example 62:

[0405] 1 H NMR(400MHz,DMSO-d6):δ=7.76(s,1H),7.37–7.28(m,5H),5.18(s,1H),5.05(d,J=12.7Hz,1H),5.00(d,J=12.7Hz,1H),4.01(d,J=5.5Hz,1H),3.53(dt,J=9.0,4.6Hz,1H),3.20(dd,J=18.8,9.6Hz,1H),2.95–2.87(m,1H),2.78(dd,J=12.9,11.2Hz,2H),2.62(dd,J=16.7,7.8Hz,1H),1.97(dd,J=14.7,11.4Hz,1H),1.78(s,2H),1.67–1.60(m,3H),1.56(dd,J=15.2,6.7Hz,3H),1.47(d,J=3.9Hz,2H),1.44(s,1H),1.39–1.26(m,4H),1.23(s,1H),1.17–1.12(m,2H),1.07(d,J=10.6Hz,4H),0.98(d,J=13.3Hz,1H),0.91(d,J=4.7Hz,3H),0.86(s,6H),0.82(s,3H),0.69(d,J=8.1Hz,4H),0.52(s,3H)ppm。

[0406] 13 C NMR(151MHz,DMSO-d6)δ=176.4,143.4,136.8(q,J C-F =36.2Hz),136.4,128.5,128.0,127.8,121.6(q,J C-F =267.3Hz),122.1,86.3,70.6,65.4,60.6,55.0,47.1,46.2,45.5,41.3,41.1,38.9,38.5,37.8,36.6,33.2,32.8,32.4,32.3,32.1,30.5,28.1,27.1,25.7,23.44,23.0,22.7,22.2,17.9,16.7,16.4,15.2ppm。

[0407] 19 F NMR(376MHz,DMSO-d6):δ=-64.92(d,J C-F =33.8Hz,3F)ppm。

[0408] HRMS (ESI): calcd for C 42 H 60 O3N2F3[M+H] + : 697.4523, found 697.4518.

[0409] Example 63 in

[0410] 1 H NMR (400 MHz, DMSO-d6): δ = 8.12 - 8.06 (m, 3H), 7.96 (s, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.77 - 7.75 (m, 1H), 7.61 - 7.58 (m, 3H), 7.53 - 7.49 (t, J = 7.5 Hz, 1H), 4.24 - 4.17 (m, 1H), 4.05 - 4.01 (m, 1H), 3.93 - 3.89 (m, 1H), 2.93 - 2.86 (m, 1H), 2.76 - 2.70 (m, 1H) ppm.

[0411] 13 C NMR (151 MHz, DMSO-d6): δ = 174.1, 155.7, 155.0, 139.6, 137.6 (q, J = 36.0 Hz), 134.4, 131.2, 130.4, 128.8, 128.7, 125.3, 125.1, 123.6, 121.4 (q, J = 268.4 Hz), 118.6, 72.5, 60.3, 32.1 ppm.

[0412] 19 F NMR (376 MHz, DMSO-d6): δ = -64.95 (s, 3F) ppm.

[0413] HRMS (ESI): calcd for C 20 H 16 O3N2F3[M+H] + : 389.1174, found 389.1168.

[0414] Example 63 in

[0415] 1H NMR (400 MHz, DMSO-d6): δ = 8.12 (dd, J = 8.0, 1.3 Hz, 1H), 8.03 - 8.01 (m, 2H), 7.87 - 7.83 (m, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.62 - 7.60 (m, 3H), 7.55 - 7.50 (m, 2H), 6.72 (s, 1H), 4.48 - 4.39 (m, 1H), 4.12 - 4.09 (m, 1H), 4.03 - 4.00 (m, 1H), 3.49 - 3.47 (m, 1H) ppm.

[0416] 13 C NMR (151 MHz, DMSO-d6): δ = 173.9, 156.0, 155.0, 142.5, 139.2, 134.4, 131.3, 130.3, 128.8, 128.6, 127.8 (q, J = 268.4 Hz), 125.4, 125.1, 123.6, 118.7, 69.8, 59.6 (q, J = 29.2 Hz), 49.6 ppm.

[0417] 19 F NMR (376 MHz, DMSO-d6): δ = -74.25 (d, J = 7.8 Hz, 3F) ppm.

[0418] HRMS (ESI): calcd for C 20 H 16 O3N2F3[M+H] + : 389.1174, found 389.1168.

[0419] Example 64:

[0420] 1 H NMR (400 MHz, DMSO-d6): δ = 7.81 (s, 1H), 5.81 - 5.80 (m, 1H), 4.65 - 4.64 (m, 1H), 4.24 (q, J = 6.3 Hz, 1H), 4.05 - 3.95 (m, 3H), 3.86 - 3.85 (m, 1H), 3.79 - 3.75 (m, 1H), 3.63 - 3.59 (m, 1H), 3.47 - 3.43 (m, 1H), 2.96 - 2.89 (m, 1H), 2.69 - 2.62 (m, 1H), 1.39 - 1.32 (m, 6H), 1.26 - 1.25 (m, 6H) ppm.

[0421] 13C NMR (151 MHz, DMSO-d6): d = 137.3 (q, J = 35.9 Hz), 121.5 (q, J = 268.3 Hz), 111.0, 108.2, 104.8, 82.2, 81.6, 80.5, 72.2, 71.1, 66.2, 60.1, 32.1, 26.7, 26.7, 26.1, 25.2 ppm.

[0422] 19 F NMR (376 MHz, DMSO-d6): d = -64.88 (s, 3F) ppm.

[0423] HRMS (ESI): calcd for C 17 H 26 O6N2F3[M+H] + : 411.1807, found 411.1799.

[0424] Example 65 in

[0425] 1 H NMR (400 MHz, DMSO-d6): d = 7.99 (s, 1H), 7.56 - 7.51 (m, 2H), 7.41 - 7.40 (m, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.46 - 6.45 (m, 1H), 4.33 - 4.24 (m, 3H), 2.92 - 2.85 (m, 1H), 2.61 - 2.55 (m, 1H) ppm.

[0426] 13 C NMR (151 MHz, DMSO-d6): d = 137.5 (q, J = 36.0 Hz), 136.1, 129.1, 128.2, 121.4 (q, J = 268.5 Hz), 121.3, 120.6, 119.3, 110.0, 101.2, 61.3, 48.1, 32.9 ppm.

[0427] 19 F NMR (376 MHz, DMSO-d6): d = -64.97 (s, 3F) ppm.

[0428] HRMS (ESI): calcd for C 13 H 13 N3F3[M+H] + : 268.1223, found 268.1217.

[0429] Example 65 in

[0430] 1 H NMR (400 MHz, DMSO-d6): δ = 7.56 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.48 - 6.47 (m, 1H), 5.06 (s, 2H), 4.31 - 4.23 (m, 1H), 2.79 - 2.72 (m, 1H), 2.55 - 2.52 (m, 1H) ppm.

[0431] 13 C NMR (151 MHz, DMSO-d6): δ = 150.1, 136.0, 129.0, 128.4, 125.9 (q, J = 278.0 Hz), 121.4, 120.6, 119.4, 110.0, 101.4, 58.7 (q, J = 29.4 Hz), 44.6, 34.1 ppm.

[0432] 19 F NMR (376 MHz, DMSO-d6): δ = -74.87 (d, J = 7.7 Hz, 3F) ppm.

[0433] HRMS (ESI): calcd for C 13 H 13 N3F3 [M+H] + : 268.1223, found 268.1217.

[0434] Example 66 in

[0435] 1 H NMR (400 MHz, DMSO-d6): δ = 8.37 (d, J = 7.3 Hz, 2H), 7.98 - 7.92 (m, 3H), 7.82 (t, J = 7.3 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 4.90-4.83 (m, 1H), 4.77 - 4.71 (m, 1H), 4.50 - 4.48 (m, 1H), 3.19 - 3.12 (m, 1H), 2.86 - 2.79 (m, 1H) ppm.

[0436] 13C NMR (151 MHz, DMSO-d6): δ = 176.7, 138.4 (q, J = 36.0 Hz), 134.0, 126.8, 121.9, 121.5, 121.1 (q, J = 268.8 Hz), 60.2, 47.5, 33.2 ppm.

[0437] 19 F NMR (376 MHz, DMSO-d6): δ = -64.90 (s, 3F) ppm.

[0438] HRMS (ESI): calcd for C 18 H 15 ON3F3 [M+H] + : 346.1179, found 346.1170.

[0439] Example 66

[0440] 1 H NMR (400 MHz, DMSO-d6): δ = 8.35 (d, J = 7.8 Hz, 2H), 7.82 - 7.75 (m, 4H), 7.35 - 7.30 (m, 3H), 5.39 (s, 2H), 4.36 (d, J = 8.0 Hz, 1H), 3.23 - 3.16 (m, 1H), 3.01 - 2.95 (m, 1H) ppm.

[0441] 13 C NMR (151 MHz, DMSO-d6): δ = 176.8, 149.0, 142.2, 134.2, 126.7, 126.0 (q, J = 278.3 Hz), 121.7, 121.5, 116.4, 59.1 (q, J = 29.3 Hz), 45.0, 34.5 ppm.

[0442] 19 F NMR (376 MHz, DMSO-d6): δ = -74.64 (d, J = 7.7 Hz, 3F) ppm.

[0443] HRMS (ESI): calcd for C 18 H 15 ON3F3 [M+H] + : 346.1179, found 346.1170.

[0444] Example 67:

[0445] 1H NMR (400MHz, DMSO-d6): δ=7.84(s,1H),7.14(s,2H),7.13(s,3H),7.11(s,1H),6.96–6.92(m,2H),4.02–3.94(m,1H),3.8 5(dd,J=13.1,6.2Hz,1H),3.65(dd,J=13.0,7.1Hz,1H),3.11(s,4H),2.91–2.84(m,1H),2.65(dd,J=16.9,8.0Hz,1H)ppm.

[0446] 13 C NMR (151MHz, DMSO-d6): δ = 148.0, 137.5 (q, J C-F =36.2Hz),134.0,130.0,126.6,123.0,121.5(q,J C-F =268.8Hz),119.9,58.8,53.4,33.7,31.5ppm.

[0447] 19 F NMR (376MHz, DMSO-d6): δ = -64.85 (s, 3F) ppm.

[0448] HRMS(ESI):calcd for C 19 H 19 N3F3[M+H] + :345.1573,found 345.1568.

[0449] The applicant declares that the preparation method of the present invention is illustrated by the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing a trifluoromethyl-substituted pyrazoline compound, characterized in that, The preparation method includes the following steps: The alkene compound shown in formula V reacts with 2,2,2-trifluorodiazoethane in the presence of a Lewis base to give trifluoromethyl-substituted pyrazoline compounds shown in formulas VI and VII, as follows: Where R is selected from The Lewis base is selected from 1,8-diazabicycloundec-7-ene; The reaction is carried out with an additional solvent added; The additional solvent is selected from any one or a combination of at least two of dichloromethane, tetrahydrofuran, or methyl tert-butyl ether; The reaction temperature is 60-80℃; The reaction time is 10-72 hours.

2. The preparation method according to claim 1, characterized in that, The 2,2,2-trifluorodiazoethane is dissolved in a stock solvent, which is selected from any one of toluene, dichloromethane, dichloroethane, methyl tert-butyl ether, or tetrahydrofuran.

3. The preparation method according to claim 1, characterized in that, The 2,2,2-trifluorodiazoethane is dissolved in a stock solvent with a molar concentration of 1.0-2.0 M.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the olefin compound shown in Formula V to 2,2,2-trifluorodiazoethane is 1:3 to 1:

5.

5. The preparation method according to claim 1, characterized in that, The amount of the Lewis base used is 5-20% of the molar amount of the olefin compound shown in Formula I.

6. The preparation method according to claim 1, characterized in that, The additional solvent is selected from methyl tert-butyl ether.

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