A method for synthesizing trifluoromethyl pyrazoline compounds

Abstract

The application relates to the technical field of organic synthesis, and particularly discloses a synthesis method of a trifluoromethyl pyrazoline compound, which comprises the following steps: adding N'-aryl trifluoromethyl bromohydrate and sulfur ylide into a solvent, then adding an alkali, and reacting at 20-30 DEG C for 1.5-2.5 h to obtain the trifluoromethyl pyrazoline compound. The application provides an efficient and mild synthesis method of a trifluoromethyl pyrazole, the construction of a trifluoromethyl pyrazole skeleton is realized through a multi-component cascade cyclization reaction of trifluoromethyl bromohydrate and sulfur ylide, the synthesis reaction condition is mild, the substrate is widely applicable, and the yield is high. The application not only provides a new way for the synthesis of the trifluoromethyl pyrazoline compound, but also lays a foundation for the structural modification and functional development of related drug molecules.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing trifluoromethylpyrazoline compounds. Background Technology

[0002] The trifluoromethylpyrazole skeleton, as an important class of fluorinated heterocyclic structures, is widely distributed in various bioactive molecular structures, including natural products, bioactive molecules, and drug molecules. For example, the anti-inflammatory drug Celecoxib (Kamil Świątek, GretaUtecht-Jarzyńska, etc. One-Pot Synthesis of 1-Aryl-3-trifluoromethylpyrazoles Using Nitrile Imines and Mercaptoacetaldehyde As a Surrogate of Acetylene[J]. Org. Lett 2023, 25, 4462−4467.), anticoagulant Razaxaban, anticancer drug SNX-5422, insecticide Pyroxasulfone, and fungicide Penthiopyrad (Hu Ma, Danfeng Huang, etc. Synthesis of 3-Trifluoromethylpyrazole Derivatives [J]. Chin. J. Org. Chem. 2023, 43, 3257-3267, etc. Figure 1 Introducing trifluoromethyl groups into heterocyclic molecules can significantly improve the physicochemical properties and pharmacological activities of the parent compound, including increasing electronegativity, enhancing bioavailability, improving metabolic stability, and regulating lipophilicity. Therefore, the research on synthetic methods for trifluoromethylpyrazole compounds has always been a hot topic in the field of organic synthesis, and the study of efficient synthetic methods for trifluoromethylpyrazole compounds has significant theoretical research value and practical application value.

[0003] Since their discovery, nitrile imides have been widely used in cycloaddition reactions. As a dual-N-atom synthon, they can rapidly construct pyrazole skeletons, greatly facilitating the synthesis of natural products and active drug structures. Trifluoromethylnitrile imides, in particular, attach a trifluoromethyl group to the pyrazole structure. The trifluoromethyl group acts as the active structure in many drug fragments, greatly simplifying the construction of trifluoromethylpyrazole derivatives. 1,3-Dipole cycloaddition reactions are a classic method for synthesizing five-membered heterocyclic compounds. The [3+2] cycloaddition reaction involving nitrile imides is one of the important methods for synthesizing pyrazole compounds. Fang Ling, He Yiyi, et al. (Regioselective Synthesis of Triaryl-substituted Fluorinated Pyrazoles, Chemical Bulletin, 2017, 5, 466-470) reported a base-promoted [3+2] dipole cycloaddition reaction of a trifluoromethyl-substituted alkyne with an in-situ generated nitrile imide. This reaction is characterized by its simple operation and good functional group compatibility, and can yield trifluoromethyl-substituted pyrazole heterocyclic compounds in moderate to good yields with excellent regioselectivity. However, this reaction depends on alkynes with specific structures, which limits the substrate range and yield. Furthermore, it requires the reaction to be carried out at 80°C. Efficiently introducing trifluoromethyl groups under mild conditions remains a challenge. Therefore, developing a simple, mild, widely applicable, and high-yield method for synthesizing trifluoromethylpyrazole is of significant research importance. Summary of the Invention

[0004] To address the above shortcomings, this invention provides a method for synthesizing trifluoromethylpyrazoline compounds, which enables efficient synthesis of trifluoromethylpyrazoline compounds under mild conditions and has a wide range of applicable substrates. The specific technical solution is as follows: A method for synthesizing a trifluoromethylpyrazoline compound includes: adding N′-aryltrifluoromethylbromohydrazone 1 and thioyl ylide 2 to a solvent, then adding a base, and reacting at 20~30℃ for 1.5~2.5h to obtain trifluoromethylpyrazoline compound 3; The structural formula of N′-aryltrifluoromethylbromohydrazone 1 is as follows: ; The structural formula of the sulfur ylide 2 is as follows: The structural formula of the trifluoromethylpyrazoline compound 3 is as follows: ; Wherein, the R 1 It is hydrogen, halogen, alkyl, methoxy, sulfonamide, cyano, or trifluoromethyl; The R 2 It is a phenyl, substituted phenyl, alkyl, naphthyl, thiophenyl, or furanyl group, wherein the substituent in the substituted phenyl group is methyl (alkyl), methoxy, halogen, cyano, or nitro.

[0005] The synthetic route for trifluoromethylpyrazoline compounds in the technical solution of this invention is as follows: .

[0006] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the solvent is chloroform, dichloromethane, diethyl ether, tetrahydrofuran, acetone, or N,N-dimethylformamide.

[0007] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the solvent is dichloromethane.

[0008] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the base is potassium carbonate (K2CO3), pyridine, triethylenediamine (DABCO), triethylamine (Et3N), cesium carbonate (Cs2CO3), potassium hydroxide (KOH), and potassium tert-butoxide (KOtBu).

[0009] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the base is triethylamine.

[0010] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the molar ratio of N′-aryltrifluoromethylbromohydrazone 1, thioyl ylide 2, and the base is 1:2.4~3.2:1~1.5.

[0011] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the molar ratio of N′-aryltrifluoromethylbromohydrazone 1, thioyl ylide 2, and the base is 1:3:1.2.

[0012] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the ratio of N′-aryltrifluoromethylbromohydrazone 1 to the solvent is 1 mmol: 5~15 mL.

[0013] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, the ratio of N′-aryltrifluoromethylbromohydrazone 1 to the solvent is 1 mmol: 10 mL.

[0014] Preferably, in the above-mentioned method for synthesizing trifluoromethylpyrazoline compounds, R... 1 It can be hydrogen, halogen, methyl (alkyl) or methoxy.

[0015] On the other hand, the present invention also provides a trifluoromethylpyrazoline compound, which is prepared by the synthetic method according to any one of claims 1 to 8.

[0016] Compared with the prior art, the beneficial effects of the present invention are: This invention develops an efficient and mild method for the synthesis of trifluoromethylpyrazole. The trifluoromethylpyrazole skeleton is constructed through a multi-component tandem cyclization reaction of trifluoromethyl bromide hydrazone and thioyl ylide. The synthesis is carried out at room temperature and in air, under mild conditions. The reaction exhibits good adaptability to various substituted aryl bromide hydrazones and thioyl ylides. It also demonstrates good compatibility with various electron-donating groups, halogens, and substituents with certain directional hindrance on aryl trifluoromethyl bromide hydrazones. Furthermore, it shows excellent versatility for aryl, fused-ring, heterocyclic, and alkyl thioyl ylides with different electron substitutions, indicating a wide range of applicable substrates. The yield reaches 80%, with high product yield. After system condition optimization, the optimal conditions were determined to be triethylamine as the base, dichloromethane as the solvent, and a reactant ratio of 1:3, achieving a target product yield as high as 95%. This invention not only provides a new route for the synthesis of trifluoromethylpyrazole compounds but also lays the foundation for the structural modification and functional development of related drug molecules. Attached Figure Description

[0017] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 The present invention relates to the drug molecular structure containing a trifluoromethylpyrazole backbone disclosed in the prior art. Detailed Implementation

[0019] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. Unless otherwise defined, all technical terms used below have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of protection of the present invention. Unless otherwise specifically stated, all raw materials, reagents, instruments, and equipment used in the present invention are commercially available or can be prepared by existing methods.

[0020] Example 1 This embodiment provides a method for synthesizing trifluoromethylpyrazoline compounds, comprising: adding 0.2 mmol of N′-aryltrifluoromethylbromohydrazone 1a and the corresponding thioyl ylide 2a (Table 1) to a solvent, then adding a base, and reacting at room temperature for 2 h until thin-layer chromatography (TLC) shows the disappearance of starting material 1a. Subsequently, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (petroleum ether (PE) and ethyl acetate (EA) = 10 / 1) to obtain trifluoromethylpyrazoline compound 3aa. The synthetic route is as follows: .

[0021] This embodiment optimizes different reaction conditions, including solvent type, base type and raw material amount, etc. The conditions for different reaction groups are listed in Table 1.

[0022] Table 1. Yields with different raw materials, dosages, and yields Table 1 shows that the reaction conditions were optimized using trifluoromethylbromophenylhydrazone 1a and thioylide 2a as template substrates. First, the solvents used in the reaction were screened, including chloroform, dichloromethane, diethyl ether, tetrahydrofuran, acetone, methanol, acetonitrile, and N,N-dimethylformamide. It was found that, except for methanol, the product could be obtained in all other solvents. However, the yield was generally low in highly polar solvents. Dichloromethane yielded the target product in 55% of the solvent. Next, the bases were screened, exploring different bases such as pyridine, DABCO, triethylamine, cesium carbonate, potassium hydroxide, and potassium tert-butoxide. All the bases used yielded the target product, with triethylamine yielding it in 80%, superior to other bases. The amount of solvent was also explored; the yield of the target product decreased when the amount of dichloromethane was 1 mL or 3 mL. Meanwhile, the dosage of raw material 2a was screened, and it was found that when its dosage was increased to 3 equivalents, the yield increased to 95%. Therefore, the optimal synthesis conditions were determined to be group 19 in Table 1.

[0023] The NMR data of the trifluoromethylpyrazoline compound 3aa in this embodiment are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.55(t, J = 7.4 Hz, 1H), 7.47 – 7.36 (m, 6H), 7.18 (dt, J = 18.4, 9.4 Hz, 6H), 6.98(t, J = 7.3 Hz, 1H).13 C NMR (100 MHz, CDCl3) δ 192.3, 157.0, 139.2, 137.6,136.8, 134.1, 131.9 (q, 2 J C-F = 37.4 Hz), 128.8, 128.8, 128.7, 128.7, 128.1,125.7, 124.2, 121.1 (q, 1 J C-F = 270.7 Hz), 117.5, 116.0, 98.1. 19 F NMR (377 MHz, CDCl3) δ -63.18. HRMS (ESI) calcd. for C 24 H 17 F3N2O2[(M + Na) + ] 445.1140, found:445.1137. Example 2 This embodiment provides a method for synthesizing trifluoromethylpyrazoline compounds, comprising: mixing 0.2 mmol of N′-aryltrifluoromethylbromohydrazone 1 and 0.6 mmol of 2-(dimethyl-λ) 4 (-thionyl)-1-phenylethane-1-one 2a was added to 2 mL of dichloromethane, followed by the addition of 0.24 mmol of triethylamine. The reaction was carried out at room temperature for 2 h until thin-layer chromatography (TLC) showed the disappearance of starting material 1a. Subsequently, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether (PE) and ethyl acetate (EA) = 10 / 1) to give trifluoromethylpyrazoline compound 3. The synthetic route, specific structure, and yield of trifluoromethylpyrazoline compound 3 are as follows: .

[0024] As can be seen from the above, when the amine of the trifluoromethyl bromide hydrazone (1) molecule is attached to a phenyl group, or when the attached phenyl group has an electron-donating group or a halogen atom at the para position (3aa-3fa), the reaction proceeds smoothly and the target product is obtained in high yield, with some products reaching yields of over 90%. However, the reaction is not tolerated when the aryl group has a strong electron-withdrawing group at the para position, such as -CN, -CF3 (3ga, 3ha). This may be because the electron-withdrawing effect of the strong electron-withdrawing group causes the electron cloud to shift and the density to decrease, resulting in a lower yield of the target product. When different substituents (3ba, 3fa, 3ia-3la) are attached to the ortho, meta, and para positions on the benzene ring, regardless of whether they are methyl or halogen groups, their position on the benzene ring has little effect on the reaction yield, and the target product can be obtained in yields higher than 80%.

[0025] Example 3 This embodiment provides a method for synthesizing a trifluoromethylpyrazoline compound, comprising: adding 0.2 mmol of N′-aryltrifluoromethylbromohydrazone 1a and 0.6 mmol of thioylide 2 to 2 mL of dichloromethane, then adding 0.24 mmol of triethylamine, and reacting at room temperature for 2 h until thin-layer chromatography (TLC) shows the disappearance of starting material 1a. Subsequently, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (petroleum ether (PE) and ethyl acetate (EA) = 10 / 1) to obtain trifluoromethylpyrazoline compound 3. The synthetic route, specific structure, and yield of trifluoromethylpyrazoline compound 3 are as follows: .

[0026] Among them, trifluoromethylpyrazoline compounds 3ab and 3ac, with methyl and methoxy electron-donating groups attached to the para-position of the benzene ring, respectively, and trifluoromethylpyrazoline compounds 3ad-3ah, with halogen, cyano, and phenyl electron-withdrawing groups attached to the para-position of the benzene ring, respectively, all exhibited high yields (85%–97%). Substituents at the meta or ortho positions (3ai–3am) also yielded the corresponding products in high yields, indicating that steric hindrance had little effect on the reaction. Fused rings and heterocycles (3an–3ap) also yielded the corresponding products in excellent yields (78%–95%). Furthermore, alkane-substituted substrates showed good tolerance; when the aromatic hydrocarbon was replaced with the alkane 3aq, the corresponding product was obtained in a 62% yield.

[0027] Example 4 This embodiment provides a method for the scaled-up synthesis of trifluoromethylpyrazoline compounds, as well as the derivatization of trifluoromethylpyrazoline compounds.

[0028] A scaled-up synthesis of a trifluoromethylpyrazoline compound includes: adding 3.75 mmol of N′-aryltrifluoromethylbromohydrazone 1a and 11.25 mmol of thioylide 2a to 37.5 mL of dichloromethane, followed by the addition of 4.5 mmol of triethylamine. The reaction is carried out at room temperature for 2 h until thin-layer chromatography (TLC) shows the disappearance of starting material 1a. Subsequently, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography (petroleum ether (PE) and ethyl acetate (EA) = 10 / 1) to give trifluoromethylpyrazoline compound 3aa in 80% yield.

[0029] Scale-up experiments were conducted under standard conditions, yielding the product in 80% yield, further demonstrating the practicality of the method.

[0030] To further verify the practicality of this synthetic method, the -OH group and double bond of 3aa were reduced under Pd / C, H2 conditions. Due to the increased stability of the five-membered ring skeleton, product 6(b) was obtained under aromatization-driven conditions, with a yield of 90%. Halogen substitution of the -OH group yielded chlorinated product 7(c) in 82% yield. Protection of the hydroxyl group with Boc yielded the corresponding product 8(d) in 80% yield. This method can also be used to rapidly construct Celecoxib analogs, obtaining product 10(e) in 67% yield, demonstrating the feasibility of this method in practical applications.

[0031] The synthetic route, derivatization route, and derived structure of trifluoromethylpyrazoline compound 3aa are as follows: The possible reaction mechanism of the technical solution of the present invention is as follows: ; First, trifluoromethyl bromide hydrazone loses one molecule of hydrogen bromide under the action of triethylamine to generate trifluoromethyl nitrile imine intermediate I. Then, it is attacked by thioylide to form zwitterionic intermediate II. Since zwitterionic intermediate II is unstable, it spontaneously loses dimethyl sulfide to transform into intermediate III. Then, intermediate III is attacked by another molecule of thioylide to form intermediate IV. Through intramolecular nucleophilic addition, it forms five-membered ring intermediate V. This intermediate undergoes proton migration and loses dimethyl sulfide again in a cascade manner to give product 3aa.

[0032] In summary, the method for synthesizing trifluoromethylpyrazoline compounds of the present invention has the advantages of mild conditions, simple operation, wide substrate applicability, and high yield.

[0033] The NMR characterization data of the synthesized compounds are as follows: ( Z)-2-(5-hydroxy-5-phenyl-1-(p-tolyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ba) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 82% yield, Mp 135-140 o C. 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.82 – 7.71 (m, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 – 7.34 (m, 4H), 7.30 (d, J = 8.5 Hz, 2H), 7.19 (dd, J = 10.1,4.7 Hz, 2H), 7.14-7.11 (m, 2H), 6.97 (d, J = 8.3 Hz, 2H), 2.21 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 192.3, 157.2, 137.7, 136.9, 136.9, 134.0, 134.0, 131.4 (q, 2 J C-F = 36.36 Hz), 129.3, 128.8, 128.8, 128.7, 128.0, 125.7, 121.2 (q, 1 J C-F =270.7 Hz), 117.7, 115.5, 98.2, 20.8. 19 F NMR (377 MHz, CDCl3) δ -63.07. HRMS(ESI) calcd. for C 25 H 19 F3N2O2[(M + Na) + ] 459.1296, found: 459.1299. ( Z )-2-(5-hydroxy-1-(4-methoxyphenyl)-5-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ca) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1), red solid, 84% yield, Mp 132-136 o C. 1 H NMR (400 MHz, CDCl3) δ7.89 (d, J = 3.9 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.57 – 7.49 (m, 1H), 7.45 – 7.34(m, 4H), 7.34 – 7.27 (m, 2H), 7.26 – 7.07 (m, 4H), 6.78 – 6.67 (m, 2H), 3.69(s, 3H). 13 C NMR (100 MHz, CDCl3) δ 192.2, 157.2, 156.9, 137.8, 137.0, 133.9,132.9, 131.1 (q, 2 J C-F = 37.37 Hz), 128.8, 128.7, 128.7, 128.0, 125.7, 121.2 (q, 1 J C-F = 270.2 Hz), 119.9, 115.3, 113.9, 98.5, 55.3. 19 F NMR (377 MHz, CDCl3) δ -63.01. HRMS (ESI) calcd. for C 25 H 19 F3N2O3[(M + Na) + ] 475.1245, found: 475.1248. ( Z)-2-(1-(4-fluorophenyl)-5-hydroxy-5-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3da) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 91% yield, Mp 128-131 o C. 1 H NMR (400 MHz, CDCl3) δ7.84 (s, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43-7.35 (m,6H), 7.22-7.12 (m, 4H), 6.90 – 6.78 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 192.3,159.7 (d, J = 244.1 Hz), 156.7, 137.5, 136.8, 135.6 (d, J = 2.7 Hz), 134.1, 132.1(q, J = 38.4 Hz), 129.0, 128.8, 128.7, 128.1, 125.7, 121.0 (q, J = 270.2 Hz),119.5 (d, J = 8.0 Hz), 116.3, 115.5 (d, J = 22.9 Hz), 98.1. 19 F NMR (377 MHz,CDCl3) δ -63.22, -118.26. HRMS (ESI) calcd. for C 24 H 16 F4N2O2[(M + Na) + ]463.1046, found: 463.1042. ( Z)-2-(1-(4-chlorophenyl)-5-hydroxy-5-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ea) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid,93% yield, Mp 135-138 o C. 1 H NMR (400 MHz, CDCl3) δ7.85 (s, 1H), 7.77 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8Hz, 2H), 7.38 – 7.32 (m, 4H), 7.24 – 7.10 (m, 6H). 13 C NMR (100 MHz, CDCl3) δ192.3, 156.5, 137.8, 137.3, 136.7, 134.2, 132.5 (q, 2 J C-F = 37.5 Hz), 129.3,129.0, 128.8, 128.8, 128.7, 128.2, 125.7, 120.9 (q, 1 J C-F = 269.9 Hz), 118.5,116.7, 97.9. 19 F NMR (377 MHz, CDCl3) δ -63.28. HRMS (ESI) calcd. forC 24 H 16 ClF3N2O2[(M + Na) + ] 479.0750, found: 479.0750. ( Z)-2-(1-(4-bromophenyl)-5-hydroxy-5-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3fa) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 85% yield, Mp 132-137 o C. 1 H NMR (400 MHz, CDCl3) δ7.86 (s, 1H), 7.79 – 7.72 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8 Hz,2H), 7.38 – 7.33 (m, 2H), 7.33 – 7.24 (m, 4H), 7.23 – 7.12 (m, 4H). 13 C NMR(100 MHz, CDCl3) δ 192.3, 156.4, 138.3, 137.3, 136.7, 134.2, 132.6 (q, 2 J C-F =37.6 Hz), 131.7, 129.0, 128.8, 128.8, 128.2, 125.7, 120.9 (q, 1 J C-F = 270.3 Hz),118.8, 117.0, 116.7, 97.9. 19 F NMR (377 MHz, CDCl3) δ -63.29. HRMS (ESI) calcd.for C 24 H 16 BrF3N2O2[(M + Na) + ]523.0245, found: 523.0247. ( Z)-4-(5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)benzonitrile(3ga) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 44% yield, Mp 140-143 o C. 1 H NMR (400 MHz, CDCl3) δ7.81 (s, 1H), 7.79 – 7.75 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 – 7.40 (m,6H), 7.38 – 7.33 (m, 2H), 7.28 – 7.15 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ192.3, 155.5, 142.3, 136.9, 136.4, 134.6 (q, 2 J C-F = 38.4 Hz), 134.6, 133.0,129.3, 128.9, 128.8, 128.4, 125.7, 120.5 (q, 1 J C-F = 270.4 Hz), 119.0, 118.3,116.5, 106.2, 97.4. 19 F NMR (377 MHz, CDCl3) δ -63.56. HRMS (ESI) calcd. forC 25 H 16 F3N3O2[(M + Na) + ] 470.1092, found: 470.1096. ( Z)-2-(5-hydroxy-5-phenyl-3-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ha) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 50% yield, Mp 122-125 o C. 1 H NMR (400 MHz, CDCl3) δ7.84 (s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 8.7Hz, 2H), 7.43 (dd, J = 8.0, 5.7 Hz, 4H), 7.38 (d, J = 7.4 Hz, 2H), 7.25-7.15 (m,4H). 13 C NMR (100 MHz, CDCl3) δ 192.4, 156.1, 141.7, 137.2, 136.5, 134.4, 133.6(q, J = 37.6 Hz), 129.1, 128.9, 128.8, 128.3, 126.0 (q, J = 3.7 Hz), 125.7, 125.3(q, J = 32.3 Hz), 124.2 (q, J = 272.7 Hz), 120.8 (q, J = 270.3 Hz), 117.5, 116.4,97.6. 19 F NMR (377 MHz, CDCl3) δ -62.04, -63.44. HRMS (ESI) calcd. forC 25 H 16 F6N2O2[(M + H) +] 491.1194, found: 491.1201. ( Z )-2-(5-hydroxy-5-phenyl-1-(m-tolyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ia) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 84% yield, Mp 116-120 o C. 1 H NMR (400 MHz, CDCl3) δ7.89 (s, 1H), 7.80 – 7.69 (m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.44 – 7.35 (m,4H), 7.26 (s, 1H), 7.23 – 7.09 (m, 5H), 7.03 (t, J = 7.9 Hz, 1H), 6.78 (d, J =7.5 Hz, 1H), 2.23 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 192.3, 157.1, 139.2,138.7, 137.8, 136.9, 134.1, 131.8 (q, 2 J C-F = 37.3 Hz), 128.8, 128.8, 128.8,128.5, 128.1, 125.8, 125.2, 121.2 (q, 1 J C-F = 268.8 Hz), 118.2, 115.9, 114.7,98.2, 21.5. 19 F NMR (377 MHz, CDCl3) δ -63.08. HRMS (ESI) calcd. for C 25 H 19 F3N2O2[(M + Na) +] 459.1296, found: 459.1291. ( Z )-2-(1-(3-bromophenyl)-5-hydroxy-5-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ja) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 80% yield, Mp 120-125 o C. 1 H NMR (400 MHz, CDCl3) δ7.82 (s, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 1.8 Hz, 1H), 7.54 (t, J = 7.4Hz, 1H), 7.38 (dd, J = 15.7, 7.7 Hz, 4H), 7.31 (dd, J = 8.2, 1.1 Hz, 1H), 7.22-7.12 (m, 4H), 7.06 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.1 Hz, 1H). 13 C NMR (100 MHz,CDCl3) δ 192.2, 156.3, 140.3, 137.2, 136.6, 134.3, 133.0 (q, 2 J C-F = 37.7 Hz),129.9, 129.0, 128.8, 128.8, 128.2, 126.8, 125.7, 122.5, 120.8 (q, 1 J C-F = 270.3Hz), 120.1, 117.0, 115.6, 97.8. 19F NMR (377 MHz, CDCl3) δ -63.28. HRMS (ESI)calcd. for C 24 H 16 BrF3N2O2[(M + Na) + ] 523.0245, found: 523.0245. ( Z )-2-(5-hydroxy-5-phenyl-1-(o-tolyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3ka) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 80% yield, Mp 115-120 o C. 1 H NMR (400 MHz, CDCl3) δ7.84 – 7.78 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.37 (d, J = 0.6 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.19 (s, 1H), 7.16-7.12 (m, 5H), 7.07(d, J = 7.5 Hz, 2H), 1.97 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 192.2, 155.9,138.2, 137.4, 137.2, 136.7, 133.9, 131.2, 130.5 (q, 2 J C-F = 37.3 Hz), 128.9,128.8, 128.6, 128.3, 128.1, 128.0, 125.8, 125.5, 121.3 (q, 1 J C-F = 269.4 Hz),116.3, 98.8, 18.2.19 F NMR (377 MHz, CDCl3) δ -63.01. HRMS (ESI) calcd. forC 25 H 19 F3N2O2[(M + Na) + ] 459.1296, found: 459.1299. ( Z )-2-(1-(2-fluorophenyl)-5-hydroxy-5-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(3la) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 80% yield, Mp 111-115 o C. 1 H NMR (400 MHz, CDCl3) δ7.79 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.38– 7.31 (m, 4H), 7.18 (s, 1H), 7.17 – 7.10 (m, 4H), 7.00 (t, J = 7.5 Hz, 1H),6.97 – 6.90 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 192.2, 157.5 (d, J = 253.9 Hz),155.5, 137.9, 136.9, 134.1, 128.9, 128.9, 128.8, 128.8, 128.7, 127.9, 127.6,127.0 (d, J = 10.7 Hz), 125.5, 123.7 (d, J = 3.9 Hz), 120.9 (q, J = 270.1 Hz),117.6, 116.5 (d,J = 20.3 Hz), 98.4. 19 F NMR (377 MHz, CDCl3) δ -63.42, -121.43.HRMS (ESI) calcd. for C 24 H 16 F4N2O2[(M + Na) + ] 463.1046, found: 463.1049. ( Z )-2-(5-hydroxy-1-phenyl-5-(p-tolyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-(p-tolyl)ethan-1-one(3ab) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 95% yield, Mp 122-127 o C. 1 H NMR (400 MHz, CDCl3) δ7.99 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 8.3Hz, 2H), 7.22 – 7.09 (m, 5H), 6.97 (d, J = 8.1 Hz, 3H), 2.37 (s, 3H), 2.15 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 191.7, 156.8, 145.3, 139.3, 138.6, 134.8,134.5, 131.9 (q, 2 J C-F = 37.4 Hz), 129.5, 128.9, 128.8, 128.7, 125.6, 124.0,121.1 (q, 1 J C-F=269.7 Hz), 117.4, 116.0, 98.1, 21.7, 21.0. 19 F NMR (377 MHz,CDCl3) δ -63.16. HRMS (ESI) calcd. for C 26 H 21 F3N2O2[(M + Na) + ] 473.1453, found:473.1457. ( Z )-2-(5-hydroxy-5-(4-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-(4-methoxyphenyl)ethan-1-one(3ac) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1), red solid, 97% yield, Mp 143-145 o C. 1 H NMR (400 MHz, CDCl3) δ8.07 (s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.8Hz, 2H), 7.18-7.13 (m, 3H), 6.95 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H),6.68 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H), 3.63 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ190.4, 164.5, 159.6, 156.2, 139.3, 131.8 (q, 2 J C-F= 36.4 Hz), 131.3, 130.1,129.9, 128.7, 127.1, 123.9, 121.2 (q, 1 J C-F =270.7 Hz), 117.4, 116.1, 114.0,113.3, 97.9, 55.5, 55.0. 19 F NMR (377 MHz, CDCl3) δ -63.15. HRMS (ESI) calcd.for C 26 H 21 F3N2O4[(M + Na) + ] 505.1351, found: 505.1349. ( Z )-1-(4-fluorophenyl)-2-(5-(4-fluorophenyl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3ad) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 96% yield, Mp 128-131 o C. 1 H NMR (400 MHz, CDCl3) δ7.87 – 7.77 (m, 3H), 7.45 – 7.30 (m, 4H), 7.19 (t, J = 8.0 Hz, 2H), 7.13-7.07(m, 3H), 7.00 (t, J = 7.4 Hz, 1H), 6.88 (t, J = 8.6 Hz, 2H). 13 C NMR (100 MHz,CDCl3) δ 190.6, 166.4 (d, J = 257.9 Hz), 162.7 (d, J = 248.6 Hz), 156.9, 139.0,133.6 (d, J= 3.3 Hz), 133.1 (d, J = 2.9 Hz), 131.8 (q, J = 37.3 Hz), 131.6 (d, J =9.8 Hz), 128.8, 127.7 (d, J = 8.2 Hz), 124.5, 121.0 (q, J = 269.7 Hz), 117.6,116.1 (d, J = 21.9 Hz), 115.8, 115.2 (d, J = 22.0 Hz), 97.7. 19 F NMR (377 MHz,CDCl3) δ -63.17, -102.17, -112.15. HRMS (ESI) calcd. for C 24 H 15 F5N2O2[(M + Na) + ]481.0951, found: 481.0955. ( Z )-1-(4-chlorophenyl)-2-(5-(4-chlorophenyl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3ae) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 93% yield, Mp 132-135 o C. 1 H NMR (400 MHz, CDCl3) δ7.79 (s, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.39 (dd, J = 7.9, 5.8 Hz, 4H), 7.31 (d, J = 8.6 Hz, 2H), 7.23 – 7.14 (m, 4H), 7.11 (s, 1H), 7.01 (t, J= 7.4 Hz, 1H). 13 CNMR (100 MHz, CDCl3) δ 190.9, 156.9, 141.1, 139.0, 136.1, 135.0, 134.9, 132.9(q, 2 J C-F = 36.4 Hz), 130.2, 129.3, 128.9, 128.4, 127.1, 124.6, 121.0 (q, 1 J C-F =270.2 Hz), 117.6, 115.5, 97.7. 19 F NMR (377 MHz, CDCl3) δ -63.15. HRMS (ESI)calcd. for C 24 H 15 C l2 F3N2O2[(M + Na) + ] 513.0360, found: 513.0348. ( Z )-1-(4-bromophenyl)-2-(5-(4-bromophenyl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3af) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 88% yield, Mp 135-140 o C. 1 H NMR (400 MHz, CDCl3) δ7.80 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 7.9Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.28 – 7.22 (m, 2H), 7.19 (t, J= 8.0 Hz, 2H),7.10 (s, 1H), 7.01 (t, J = 7.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 191.1, 156.9,138.9, 136.5, 135.4, 132.2, 131.9 (q, 2 J C-F = 37.7 Hz), 131.3, 130.2, 129.9,128.8, 127.4, 124.6, 123.2, 120.9 (q, 1 J C-F = 269.8 Hz), 117.6, 115.4, 97.8. 19 FNMR (377 MHz, CDCl3) δ -63.12. HRMS (ESI) calcd. for C 24 H 15 Br2F3N2O2[(M + H) + ]578.9531, found: 578.9534. ( Z )-4-(4-(2-(4-cyanophenyl)-2-oxoethylidene)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile(3ag) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 85% yield, Mp 135-140 o C. 1 H NMR (400 MHz, CDCl3) δ7.88 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.56 – 7.45 (m,4H), 7.37 (d, J = 8.0 Hz, 2H), 7.21 (t, J= 8.0 Hz, 2H), 7.15 (s, 1H), 7.05 (t, J =7.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 190.7, 157.4, 141.8, 139.4, 138.6,132.7, 132.1, 129.1, 129.0, 126.5, 125.3, 120.7 (q, 1 J C-F =270.7 Hz), 117.9,117.5, 117.4, 115.0, 113.2, 97.7. 19 F NMR (377 MHz, CDCl3) δ -63.10. HRMS (ESI)calcd. for C 26 H 15 F3N4O2[(M + Na) + ] 495.1045, found: 495.1049. ( Z )-1-([1,1'-biphenyl]-4-yl)-2-(5-([1,1'-biphenyl]-4-yl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3ah) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 96% yield, Mp 130-135 o C. 1 H NMR (400 MHz, CDCl3) δ8.03 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 7.1Hz, 2H), 7.47 (d, J = 8.5 Hz, 4H), 7.44 – 7.35 (m, 7H), 7.30 (t, J= 7.4 Hz, 2H),7.26 – 7.14 (m, 4H), 6.97 (t, J = 7.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 191.7,156.7, 146.9, 141.4, 139.9, 139.4, 139.2, 136.6, 135.5, 132.0 (q, 2 J C-F = 36.36Hz), 129.4, 129.0, 128.8, 128.7, 128.5, 127.5, 127.4, 127.2, 126.9, 126.7,126.2, 124.2, 121.1 (q, 1 J C-F = 270.68 Hz), 117.5, 116.1, 98.1. 19 F NMR (377 MHz,CDCl3) δ -63.00. HRMS (ESI) calcd. for C 36 H 25 F3N2O2[(M + Na) + ] 597.1766, found:597.1768. ( Z )-2-(5-hydroxy-5-(3-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-(3-methoxyphenyl)ethan-1-one(3ai) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1), red solid, 89% yield, Mp 128-132 o C. 1 H NMR (400 MHz, CDCl3) δ7.87 (s, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.38-7.29 (m, 3H), 7.18 (t, J= 8.0 Hz,2H), 7.15 – 7.06 (m, 3H), 7.00-6.92 (m, 3H), 6.70 – 6.63 (m, 1H), 3.80 (s,3H), 3.69 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ 192.0, 159.9, 159.2, 156.5,139.2, 139.2, 138.2, 132.0 (q, 2 J C-F = 36.4 Hz), 129.8, 129.2, 128.7, 124.2,121.5, 121.0 (q, 1 J C-F = 270.7 Hz), 120.5, 118.1, 117.6, 116.2, 114.1, 112.9,112.0, 97.9, 55.4, 55.2. 19 F NMR (377 MHz, CDCl3) δ -63.19. HRMS (ESI) calcd.for C 26 H 21 F3N2O4[(M + Na) + ] 505.1351, found: 505.1354. ( Z )-1-(3-chlorophenyl)-2-(5-(3-chlorophenyl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3aj) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1), red solid, 86% yield, Mp 135-148 o C. 1 H NMR (400 MHz, CDCl3) δ7.77 (t, J = 1.8 Hz, 1H), 7.72 (s, 1H), 7.70 – 7.64 (m, 1H), 7.54 (ddd,J = 8.0,2.0, 0.9 Hz, 1H), 7.41-7.37 (m, 4H), 7.29 – 7.13 (m, 5H), 7.12 (s, 1H), 7.02(t, J = 7.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 190.9, 156.9, 139.3, 138.9,138.1, 135.3, 134.3, 134.2, 131.9 (q, 2 J C-F = 37.7 Hz), 130.2, 129.4, 129.3,128.9, 128.7, 126.9, 126.0, 124.7, 123.9, 120.9 (q, 1 J C-F = 269.8 Hz), 117.7,115.5, 97.5. 19 F NMR (377 MHz, CDCl3) δ -63.10. HRMS (ESI) calcd. forC 24 H 15 Cl2F3N2O2[(M + H) + ] 491.0541, found: 491.0546. ( Z )-1-(3-bromophenyl)-2-(5-(3-bromophenyl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3ak) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 84% yield, Mp 113-120 o C. 1 H NMR (400 MHz, CDCl3) δ7.92 (s, 1H), 7.76 – 7.65 (m, 3H), 7.53 (s, 1H), 7.39 (d, J= 8.1 Hz, 2H),7.33-7.29 (m, 3H), 7.21 (t, J = 7.8 Hz, 2H), 7.13 – 6.99 (m, 3H). 13 C NMR (100MHz, CDCl3) δ 190.9, 156.9, 139.5, 138.9, 138.3, 137.1, 132.3, 132.0 (q, 2 J C-F =37.37 Hz), 131.6, 130.4, 129.7, 128.9, 127.3, 124.7, 124.4, 123.3, 122.4,120.9 (q, 1 J C-F = 271.69 Hz), 117.8, 115.6, 97.5. 19 F NMR (377 MHz, CDCl3) δ -63.08. HRMS (ESI) calcd. for C 24 H 15 Br2F3N2O2[(M + H) + ] 578.9531, found:578.9536. ( Z )-2-(5-hydroxy-5-(2-methoxyphenyl)-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-(2-methoxyphenyl)ethan-1-one(3al) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 85% yield, Mp 130-132 o C. 1 H NMR (400 MHz, CDCl3) δ8.00 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 – 7.39 (m, 2H), 7.35 (d, J= 7.8 Hz, 2H),7.17 – 7.08 (m, 4H), 7.06 (d, J = 0.8 Hz, 1H), 6.96 – 6.83 (m, 4H), 6.62 (d, J =8.1 Hz, 1H), 3.80 (s, 3H), 3.62 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 192.7,159.0, 156.2, 154.2, 140.0, 134.8, 133.6 (q, 2 J C-F = 36.7 Hz), 130.9, 130.1,129.9, 128.3, 127.3, 125.7, 123.3, 121.5 (q, 1 J C-F = 269.67 Hz), 120.8, 120.7,119.2, 117.6, 111.8, 111.4, 95.0, 55.5, 55.1. 19 F NMR (377 MHz, CDCl3) δ -63.59. HRMS (ESI) calcd. for C 26 H 21 F3N2O4[(M + Na) + ] 505.1351, found: 505.1344. ( Z )-1-(2-fluorophenyl)-2-(5-(2-fluorophenyl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3am) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 84% yield, Mp 107-113 o C. 1 H NMR (400 MHz, CDCl3) δ7.99 (td, J= 7.7, 2.2 Hz, 1H), 7.58 (td, J = 7.6, 1.8 Hz, 1H), 7.53-7.47 (m,1H), 7.42 – 7.35 (m, 2H), 7.20 – 7.04 (m, 8H), 6.97 (t, J = 7.4 Hz, 1H), 6.85 –6.76 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ190.0 (d, J = 2.8 Hz), 161.7 (d, J = 249.2Hz), 159.2 (d, J = 242.0 Hz), 155.3, 139.4, 135.8 (d, J = 9.1 Hz), 133.1 (q, J =37.7 Hz), 131.0 (d, J = 8.1 Hz), 130.9, 130.1 (d, J = 2.4 Hz), 128.6, 125.4 (d, J =11.6 Hz), 124.6 (d, J = 3.6 Hz), 124.4 (d, J = 12.9 Hz), 124.2, 122.7 (d, J = 3.0Hz), 120.9 (q, J = 271.69 Hz), 119.8 (d, J = 7.9 Hz), 117.8, 116.8 (d, J = 23.2Hz), 116.0 (d, J = 21.4 Hz), 94.4. 19 F NMR (377 MHz, CDCl3) δ -63.61, -108.53, -112.06. HRMS (ESI) calcd. for C 24 H 15 F5N2O2[(M + Na) + ] 481.0951, found: 481.0942. ( Z)-2-(5-hydroxy-5-(naphthalen-2-yl)-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-(naphthalen-2-yl)ethan-1-one(3an) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 83% yield, Mp 162-165 o C. 1 H NMR (400 MHz, CDCl3) δ8.23 (d, J = 10.1 Hz, 2H), 8.08 (s, 1H), 7.86 (dd, J = 12.9, 8.1 Hz, 2H), 7.80-7.75 (m, 3H), 7.64 (d, J = 8.4 Hz, 2H), 7.59 – 7.45 (m, 4H), 7.43-7.30 (m, 4H),7.15 (t, J = 7.8 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ192.0, 156.7, 139.2, 135.8, 134.8, 134.1, 133.1, 132.3, 132.1, 132.1 (q, 2 J C-F =37.2 Hz), 131.0, 129.8, 129.2, 128.7, 128.6, 128.4, 127.7, 127.4, 127.0,126.6, 126.4, 125.8, 124.2, 123.8, 122.7, 121.2 (q, 1 J C-F = 269.7 Hz), 117.4,116.3, 98.3. 19F NMR (377 MHz, CDCl3) δ -63.01. HRMS (ESI) calcd. forC 32 H 21 F3N2O2[(M + Na) + ] 545.1453, found: 545.1456. ( Z )-2-(5-hydroxy-1-phenyl-5-(thiophen-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-(thiophen-2-yl)ethan-1-one(3ao) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 95% yield, Mp 133-136 o C. 1 H NMR (400 MHz, CDCl3) δ8.26 (s, 1H), 7.72 (ddd, J = 5.8, 4.4, 0.9 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H),7.24 (t, J = 8.0 Hz, 2H), 7.14 – 7.10 (m, 2H), 7.10 – 7.01 (m, 3H), 6.76 (dd, J =5.0, 3.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 183.7, 155.2, 144.4, 141.4, 139.2,136.5, 134.0, 132.0 (q, 2 J C-F = 36.36 Hz), 128.8, 128.7, 126.4, 126.4, 126.3,124.8, 120.9 (q, 1 J C-F = 271.69 Hz), 118.7, 115.9, 96.9. 19F NMR (377 MHz, CDCl3)δ -63.26. HRMS (ESI) calcd. for C 20 H 13 F3N2O2S2[(M + Na) + ] 457.0268, found:457.0269. ( Z )-1-(furan-2-yl)-2-(5-(furan-2-yl)-5-hydroxy-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)ethan-1-one(3ap) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 78% yield, Mp 122-125 o C. 1 H NMR (400 MHz, CDCl3) δ8.03 (s, 1H), 7.66 (d, J = 0.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 3.7Hz, 1H), 7.25 (t, J = 8.0 Hz, 2H), 7.16 (dd, J = 6.9, 6.1 Hz, 2H), 7.05 (t, J = 7.4Hz, 1H), 6.67 – 6.50 (m, 2H), 6.20 (dd, J = 3.3, 1.8 Hz, 1H). 13 C NMR (100 MHz,CDCl3) δ 178.8, 153.8, 153.1, 148.7, 148.1, 143.0, 139.6, 132.4 (q, 2 J C-F = 37.37Hz), 128.7, 124.4, 120.8 (q, 1 J C-F= 270.68 Hz), 120.2 , 117.5, 115.8, 113.3,110.6, 110.1, 94.5. 19 F NMR (377 MHz, CDCl3) δ -63.40. HRMS (ESI) calcd. forC 20 H 13 F3N2O4[(M + Na) + ] 425.0725, found: 425.0726. ( Z )-1-(5-hydroxy-5-phenethyl-1-phenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-4-phenylbutan-2-one(3aq) Purified with silica gel chromatography (petroleum ether / ethylacetate = 10:1),red solid, 62% yield, Mp 120-123 o C. 1 H NMR (400 MHz, CDCl3) δ7.68 (d, J = 7.9 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.31 – 7.24 (m, 2H), 7.23 –7.16 (m, 4H), 7.15 – 7.09 (m, 3H), 7.07 (s, 1H), 6.73 (dd, J = 7.4, 1.7 Hz,2H), 6.34 (d, J = 0.6 Hz, 1H), 3.03 – 2.90 (m, 4H), 2.62 – 2.39 (m, 2H), 2.29 –2.10 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 203.4, 153.4, 140.1, 139.7, 139.6,132.7 (q, 2 J C-F= 37.3 Hz), 129.2, 128.6, 128.4, 128.3, 128.0, 126.4, 126.2,124.9, 120.7 (q, 1 J C-F = 269.9 Hz), 118.1, 117.2, 99.8, 45.8, 37.8, 29.9,29.5. 19 F NMR (377 MHz, CDCl3) δ -63.59. HRMS (ESI) calcd. for C 28 H 25 F3N2O2[(M +Na) + ] 501.1766, found: 501.1760. 2-(1,5-diphenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-phenylethan-1-one(4) white solid, 90% yield, Mp 125-130 o C. 1 H NMR (400 MHz, CDCl3) δ 7.97(d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.39 –7.24 (m, 8H), 7.17 (d, J = 7.0 Hz, 2H), 4.23 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ196.0, 143.9, 141.8 (q, 2 J C-F = 36.4 Hz), 139.2, 136.3, 133.4, 129.9, 129.2,128.9, 128.8, 128.7, 128.7, 128.2, 128.0, 125.1, 124.3 (q, 1 J C-F = 238.4 Hz),112.4, 33.5. 19F NMR (377 MHz, CDCl3) δ -61.15. HRMS (ESI) calcd. for C 24 H 17 F3N2O[(M + Na) + ] 429.1191, found: 429.1194. ( Z )-2-(5-chloro-1,5-diphenyl-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazol-4-ylidene)-1-phenylethan-1-one(5) red solid, 72.3 mg, 82% yield, Mp 85-90 o C. 1 H NMR (400 MHz, CDCl3) δ7.55 – 7.50 (m, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.31 (q, J =7.9 Hz, 4H), 7.27 – 7.22 (m, 3H), 7.18-7.15 (m, 2H), 7.09 (d, J = 7.3 Hz, 2H),6.43 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 189.0, 143.9, 140.5 (q, 2 J C-F = 37.2 Hz),138.4, 134.0, 133.3, 130.4, 130.0, 128.9, 128.7, 128.6, 128.4, 128.4, 127.2,125.1, 121.2 (q, 1 J C-F = 270.3 Hz), 115.2, 54.9. 19 F NMR (377 MHz, CDCl3) δ -60.29. HRMS (ESI) calcd. for C 24 H 16 ClF3N2O [(M + H) +] 441.0982, found:441.0981. ( Z )-tert-butyl (4-(2-oxo-2-phenylethylidene) -1,5-diphenyl-3-(trifluoromethyl) -4,5- dihydro-1H-pyrazol-5-yl) carbonate(6) red solid, 80% yield, Mp 100-105 o C. 1 H NMR (400 MHz, CDCl3) δ 7.43-7.33(m, 4H), 7.27 – 7.19 (m, 7H), 7.15 – 7.08 (m, 2H), 6.95-6.94 (m, 3H), 1.55(s, 9H). 13 C NMR (100 MHz, CDCl3) δ 191.2, 152.4, 145.2, 141.5 (q, 2 J C-F = 37.2Hz), 138.5, 134.3, 133.1, 130.6, 129.8, 128.9, 128.4, 128.2, 128.0, 126.8,125.2, 121.2 (q, 1 J C-F = 270.2 Hz), 112.7, 83.3, 71.0, 27.7. 19 F NMR (377 MHz,CDCl3) δ -60.71. HRMS (ESI) calcd. for C 29 H 25 F3N2O4[(M + Na) + ] 545.1664, found:545.1664. 4-(5-hydroxy-4-(2-oxo-2-(p-tolyl)ethylidene)-5-(p-tolyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide (7) Purified with silica gel chromatography (petroleum ether / ethylacetate = 15:1),yellow slime, 61% yield. 1 H NMR (400 MHz, CDCl3) δ 7.95 (s,1H), 7.67 (dd, J = 12.2, 8.6 Hz, 4H), 7.47 (d, J = 8.9 Hz, 2H), 7.21 (dd, J = 10.7,8.3 Hz, 5H), 6.99 (d, J = 8.1 Hz, 2H), 5.10 (s, 2H), 2.37 (s, 3H), 2.15 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 191.65, 155.29, 145.79, 142.46, 139.05,135.67, 134.33 (q, 2 J C-F = 37.7 Hz), 134.03, 129.54, 129.01, 128.99, 127.40,125.52, 120.61 (q, 1 J C-F = 270.4 Hz), 117.96, 116.28, 97.49, 21.76, 20.98. 19 F NMR(377 MHz, CDCl3) δ -63.49. 4-(4-(2-oxo-2-(p-tolyl)ethyl)-5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide(8) Purified with silica gel chromatography (petroleum ether / ethylacetate = 8 / 1),white solid, 67% yield, Mp 170-175 o C. 1H NMR (400 MHz, CDCl3) δ7.85 (dd, J = 15.6, 8.5 Hz, 4H), 7.41 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 9.1 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 5.01 (s, 2H), 4.18 (s, 2H), 2.42 (s, 3H), 2.34 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 195.6, 144.5,144.3, 142.8 (q, 2 J C-F = 36.9 Hz), 142.5, 140.8, 139.9, 133.6, 129.9, 129.6,129.4, 128.3, 127.3, 125.0, 125.0, 121.5 (q, 1 J C-F = 270.2 Hz), 113.5, 33.3,21.7, 21.3. 19 F NMR (377 MHz, CDCl3) δ -61.45. HRMS (ESI) calcd. forC 26 H 22 F3N3O3S [(M + Na) + ] 536.1232, found: 536.1235. The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for synthesizing trifluoromethylpyrazoline compounds, characterized in that, include: N′-aryltrifluoromethylbromohydrazone 1 and thioyl ylide 2 were added to a solvent, and then a base was added. The mixture was reacted at 20-30°C for 1.5-2.5 h to obtain trifluoromethylpyrazoline compound 3. The structural formula of N′-aryltrifluoromethylbromohydrazone 1 is as follows: ； The structural formula of the sulfur ylide 2 is as follows: The structural formula of the trifluoromethylpyrazoline compound 3 is as follows: ； Wherein, the R 1 It is hydrogen, halogen, alkyl, methoxy, sulfonamide, cyano, or trifluoromethyl; The R 2 It is a phenyl, substituted phenyl, alkylphenyl, naphthyl, thiophenyl or furanyl, wherein the substituent in the substituted phenyl is methyl (alkyl), methoxy, halogen, cyano or nitro.

2. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 1, characterized in that, The solvent is dichloromethane.

3. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 1, characterized in that, The base is triethylamine.

4. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 1, characterized in that, The molar ratio of N′-aryltrifluoromethylbromohydrazone 1, thioyl ylide 2, and the base is 1:2.4~3.2:1~1.

5.

5. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 1, characterized in that, The ratio of N′-aryltrifluoromethylbromohydrazone 1 to solvent is 1 mmol: 5~15 mL.

6. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 1, characterized in that, The R 1 It can be hydrogen, halogen, methyl, methoxy, or sulfonamide.

7. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 4, characterized in that, The molar ratio of N′-aryltrifluoromethylbromohydrazone 1, thioyl ylide 2, and the base is 1:3:1.

2.

8. The method for synthesizing trifluoromethylpyrazoline compounds according to claim 5, characterized in that, The ratio of N′-aryltrifluoromethylbromohydrazone 1 to the solvent is 1 mmol: 10 mL.

9. A trifluoromethylpyrazoline compound, characterized in that, The trifluoromethylpyrazoline compound is prepared by the synthetic method according to any one of claims 1 to 8.

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