CN114716380A - A high-efficiency phase transfer catalyzed method for asymmetric fluorination of 4-substituted pyrazolones - Google Patents

Abstract

The invention discloses a high-efficiency phase transfer catalytic 4-substituted pyrazolone compound asymmetric fluorination method, which comprises the following specific steps: uniformly stirring and mixing the 4-substituted pyrazolone compound, the phase transfer catalyst and the electrophilic fluorination reagent in a solvent, adding alkali, and stirring and reacting at-78-60 ℃ to obtain the chiral alpha-fluoropyrazolone compound. The method uses a phase transfer catalysis strategy and utilizes a cinchona alkaloid derived phase transfer catalyst to successfully realize the wide, high-efficiency and high-enantioselectivity asymmetric fluorination reaction of the 4-substituted pyrazolone compound. The method has the advantages of mild reaction conditions, simple operation, good substrate applicability, environmental friendliness and low cost, and is suitable for large-scale industrial production.

Description

A high-efficiency phase transfer catalyzed method for asymmetric fluorination of 4-substituted pyrazolones

technical field

The invention belongs to the technical field of phase transfer catalysis and organic synthesis, and in particular relates to a method for asymmetric fluorination of 4-substituted pyrazolone compounds with efficient phase transfer catalysis.

Background technique

Pyrazolones are five-membered heterocyclic compounds containing two nitrogen atoms, which are the core structures of many natural products and biologically active compounds. In particular, pyrazol-5-one compounds have insecticidal, antibacterial, analgesic, anti-inflammatory, anti-tumor and other effects, and have been found to have inhibitory effects on CD80 and the accumulation of protease-resistant prion proteins. , can also be used as cytokines, p38 kinase inhibitors, neuroprotective agents, HIV-1 integrase inhibitors and antipyretics (Progress in Chemistry, 2020, 32, 1710). On the other hand, fluorine-containing compounds are playing an increasingly important role in medicine, pesticides, life science and material science. Among the currently marketed small-molecule drugs, more than 25% of the drug molecules contain fluorine atoms (Org. Process Res. Dev.2020, 24, 470). However, fluorine atoms cannot be obtained from natural products, and the preparation of fluorine-containing chiral compounds has always been the focus and research focus of organic fluoride scientists. The introduction of chiral fluorine atoms through asymmetric catalytic methods is the most direct and effective method to obtain fluorine-containing chiral compounds (Chem. Rev., 2015, 115, 826). Among them, complex metal catalysis (J.Am.Chem.Soc. 2002, 124, 14530) and organic catalysis (Science 2011, 334, 1681) are the two most representative asymmetric fluorination schemes. However, for the important structural unit of pyrazolone, there are very few methods to introduce chiral fluorine atom through asymmetric catalysis. Ma Junan et al. first developed the asymmetric Michael addition/fluorination two-step tandem reaction of pyrazolones in 2012 to introduce a chiral fluorine atom at the 4-position of pyrazolones (Chem.Eur.J.2012,18,14255) Subsequently, Wang Baomin et al. developed an asymmetric F-C addition/fluorination two-step tandem reaction to introduce a chiral fluorine atom at the 4-position of pyrazolones (Org. Lett. 2015, 17, 5168). However, these works introduce chiral centers in the first step of the reaction, and the actual fluorination step is a diastereoselective fluorination process. In 2016, Wang Baomin et al. reported the direct asymmetric fluorination of 4-substituted pyrazolones, using cinchona quinine as a catalyst (10 mol%) and cesium carbonate as a base, but the enantioselectivity of the reaction was not high. (35-81% ee), a reaction time of 3-5 days, and an ultra-low temperature of -60°C are required. Obviously, the high catalyst dosage, harsh reaction conditions and low enantioselectivity limit the application of this method in practical production.

SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to provide a high-efficiency phase transfer catalyzed asymmetric fluorination method for 4-substituted pyrazolones. And efficient and high enantioselective asymmetric fluorination of 4-substituted pyrazolones.

The present invention adopts the following technical scheme in order to solve the above-mentioned technical problems: a high-efficiency phase transfer catalyzed 4-substituted pyrazolone compound asymmetric fluorination method is characterized in that the concrete process is: the 4-substituted pyrazolone compound Ia , phase transfer catalyst and electrophilic fluorinated reagent are stirred and mixed uniformly in the solvent, then add alkali, and stir reaction at -78～60 ℃ to obtain chiral α-fluoropyrazolone compound Ib, and the reaction equation in the preparation process is:

Wherein R ₁ is phenyl or substituted phenyl, and the substituent on the substituted phenyl benzene ring is F, Cl, Br, I, methoxy, C _1-4 alkyl, nitro, acetonitrile or trifluoromethane base, R ₂ is methyl, ethyl or substituted ethyl, the substituent on the substituted ethyl is phenyl, substituted phenyl, naphthyl or alkynyl, and the substituent on the substituted phenyl benzene ring is F, Cl , Br, I, methoxy, C _1-4 alkyl, nitro, acetonitrile or trifluoromethyl, R ₃ is C _1-4 alkyl, phenyl, substituted phenyl or naphthyl, the substituted benzene The substituents on the phenyl ring are F, Cl, Br, I, methoxy, C _1-4 alkyl, nitro, acetonitrile, O-CH ₂ -O (methylenedioxy) or trifluoro methyl;

Described phase transfer catalyst is cinchona base cinchonine derivative IIa or IIb, and its corresponding structural formula is:

wherein R ₃ is H or methoxy, R ₄ is tert-butyl, adamantyl, isopropyl, benzyl or substituted aryl;

The structural formula of the electrophilic fluorinating reagent is:

wherein R ₆ is H, methoxy, methyl, chlorine, bromine or iodine.

Further limited, the specific synthesis process of the phase transfer catalyst cinchonaine cinchonine derivative IIa or IIb is: use primary amine and bromoacetyl bromide to react to generate bromoamide, and then further react with cinchonadine in tetrahydrofuran to obtain a phase transfer catalyst Cinchona alkaloid cinchonine derivative IIa or IIb; the corresponding synthetic route is:

Further limited, the solvent is halogenated hydrocarbon, aromatic hydrocarbon, alkane or ether; preferably one or more of toluene, trifluorotoluene, chloroform, p-xylene, mesitylene or n-hexane.

Further limited, the alkali is an organic base or an inorganic alkali aqueous solution; preferably an inorganic alkali aqueous solution, the inorganic alkali aqueous solution is sodium carbonate, dipotassium hydrogen phosphate, potassium phosphate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, A combination of one or more aqueous solutions of lithium hydroxide, potassium fluoride or potassium acetate.

Further limited, the reaction temperature is -20 to 25°C.

Further limited, the amount of the phase transfer catalyst is 0.01-10 mol% of the amount of the 4-substituted pyrazolone compound Ia; preferably 0.5-1 mol%.

Further limited, the molar ratio of the electrophilic fluorination reagent to the 4-substituted pyrazolone compound Ia is 1-2:1.

Further limited, the reaction time is 10min～1h.

Compared with the prior art, the present invention has the following advantages and beneficial effects: the effectiveness of the present invention is reflected in the use of cheap and readily available chiral phase transfer catalysts, and the asymmetric electrophilicity of 4-substituted pyrazolones is successfully realized The fluorination reaction has very high yield and high enantioselectivity (up to 98% ee), and the reaction can be completed within 10min to 1h. This method provides an efficient synthetic route for the preparation of optically active α-fluoropyrazolones. In the fluorination method of the present invention, the reaction product is easily separated in the reaction system, and the fluorination efficiency can still be maintained at a high level when enlarged to the gram level. The invention has mild reaction conditions, simple operation, good substrate applicability and environmental friendliness, low cost, and is suitable for large-scale industrial production.

Detailed ways

The specific embodiments of the present invention are described in detail below in conjunction with the technical solutions, so that those skilled in the art can better understand the present invention.

Example 1

Synthesis of Bromoamides

To dichloromethane (15 mL) containing aniline (10 mmol) was added an aqueous solution (20 mL) of potassium carbonate (2.1 g, 15 mmol). Subsequently, the mixture was cooled to 0° C., and bromoacetyl bromide (1.3 mL, 15 mmol) was added to 3 mL of dichloromethane, mixed, and added dropwise, and the reaction was continued for 1 h. After the reaction, the two phases were separated, and the aqueous phase was extracted three times with dichloromethane (3×15 mL); the organic phase was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain product S1 with a yield of 95%. Bromoamides S2-S16 with different structures were also synthesized using the same method. The reaction yields and compound structures are shown below:

Example 2

Preparation of IIa-1

Cinchonine (1.0 g, 3.4 mmol) was mixed with the corresponding bromoamide (3.4 mmol), 30 mL of THF was added, heated to reflux for 2 h, and the reaction was controlled by thin layer chromatography. Dichloromethane (2 mL) was taken to dissolve all the solids after spin drying, and ether (25 mL) was added dropwise to the solution to precipitate all solids. The precipitate was suction filtered, washed with ether, and finally dried and weighed to obtain the product.

White solid, mp: 196-201°C; [α] _D ²⁵ 42.0 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.04 (d, J=5.5 Hz, 1H), 8.98 (d, J=4.5Hz, 1H), 8.25–8.02 (m, 2H), 7.87–7.70 (m, 4H), 7.60 (ddd, J=8.4, 6.8, 1.4Hz, 1H), 7.50–7.38 (m ,2H),7.21(td,J＝7.4,1.2Hz,1H), 6.79(dd,J＝15.5,3.4Hz,1H),6.21-5.91(m,2H),5.37-5.13(m,2H), 4.80(dd,J＝16.1,12.1Hz,1H),4.66(d,J＝15.9Hz,1H),4.34(dt,J＝39.0,10.2Hz,3H),3.96–3.83(m,1H),3.76 –3.59(m,1H),2.87(q,J=8.7Hz,1H),2.23(t,J=11.9Hz,1H),2.02–1.85(m,3H),1.20–0.98(m,1H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ163.22,150.65,148.05,145.14, 138.24,137.06,130.39,129.89,129.62,127.51,125.14,124.83,123.60,120.63,120.10,117.68,66.01,65.19,59.70,59.59 , 57.60, 37.58, 26.62, 23.39, 20.59, 11.76.

The implementation process of Examples 3 to 16 is the same as that of Example 2, but the phase transfer catalyst structures IIa-2 to IIa-15 listed in the following table are used instead of IIa-1, and the results are shown in Table 1.

The experimental results of the synthesized phase transfer catalysts in Table 1

The relevant melting point, optical rotation and nuclear magnetic data of the phase transfer catalyst:

IIa-2: white solid, mp: 88-92°C; [α] _D ²⁵ 92.5 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.95 (d, J=5.5 Hz, 1H), 8.99 (d, J=4.5Hz, 1H), 8.32–8.13 (m, 2H), 8.10– 7.69 (m, 6H), 7.68–7.49 (m, 3H), 7.41 (ddd, J=8.4, 6.8,1.4Hz,1H),6.90(d,J＝3.5Hz,1H),6.20(q,J＝6.5,4.8Hz,1H),6.05(ddd,J＝17.2,10.2,6.7Hz,1H), 5.38–5.21 (m, 2H), 5.06 (d, J=15.9Hz, 1H), 4.84 (dd, J=16.1, 12.1Hz, 1H), 4.58–4.21 (m, 3H), 3.98 (t, J= 11.4Hz, 1H), 3.87–3.70 (m, 1H), 3.65–3.52 (m, 2H), 2.98–2.82 (m, 1H), 2.24 (t, J=11.9 Hz, 1H), 1.96 (d, J = 8.5Hz, 3H), 1.75 (td, J=5.9, 5.2, 2.6Hz, 2H), 1.06 (d, J=8.8Hz, 1H). ¹³ CNMR (101MHz, DMSO-d ₆ ) δ 164.26, 150.65, 148.06 ,145.24,137.11,134.24,132.29, 130.32,129.86,128.77,128.28,127.43,127.05,126.84,126.77,126.05,124.87,123.70,123.13,122.91,120.62,117.67,67.48,66.11,65.42,59.57,57.56,37.60 , 26.64, 25.60, 23.43, 20.68, 11.77.

IIa-3: pale yellow solid, mp: 213-215°C; [α] _D ²⁵ 74.5 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (q, J=4.8, 3.6Hz, 1H), 8.99 (d, J=4.5Hz, 1H), 8.27 (d, J=8.5Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.93–7.66 (m, 2H) ,7.52(t,J＝7.7Hz,1H),7.30(t,J＝7.6Hz,1H),7.19(d,J＝7.6Hz,2H),6.95(dd,J＝16.5,3.9Hz,1H) ,6.20–5.95(m,2H),5.29(dd,J=14.1,3.3Hz,2H),5.04(s,1H),4.76(d,J=15.6Hz,1H),4.52–4.31(m,2H ),4.16(t,J=11.5Hz,1H),3.97(t,J=11.7Hz,1H),3.78(q,J=15.5,12.4Hz,1H),2.86(q,J=8.9Hz,1H) ), 2.66–2.44 (m, 6H), 2.13 (q, J=11.8Hz, 1H), 1.92 (dd, J=20.2, 6.8Hz, 4H), 1.31– 0.81 (m, 9H). ¹³ C NMR ( 101MHz,DMSO-d ₆ )δ164.18,150.65,148.07,145.27,141.72, 137.01,132.51,130.28,129.89,128.42,127.50,126.67,124.88,123.92,120.55,117.66, 66.21,65.28,59.59,58.86,57.01,37.60 , 26.65, 24.81, 23.38, 20.80, 15.19, 11.73.

IIa-4: white solid, mp: 196-201 °C; [α] _D ²⁵ 69.4 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (d, J=4.5 Hz, 1H), 8.47 (d, J=7.4Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 8.09 (d, J=8.3Hz, 1H), 7.90–7.73 (m, 2H), 7.71– 7.55(m,1H),6.78(dd,J=16.1,3.7Hz,1H), 6.08–5.88(m,2H),5.34–5.09(m,2H),4.57(d,J=15.9Hz,1H) ,4.45–4.19(m,4H),3.84(t,J=11.3Hz,1H),3.69–3.52(m,1H),2.81(q,J=8.8Hz,1H),2.07(q,J=11.3 , 8.1Hz, 10H), 1.89(q, J=9.4, 7.6Hz, 3H), 1.67(s, 6H), 1.03–0.93(m, 1H). ¹³ C NMR(101MHz, DMSO-d ₆ )δ163. 79,150.67,148.04,145.25,137.02,130.30,129.96,127.48,124.83,123.89,120.53,117.60,66.07,64.64,59.48,59.02,57.23,52.69,49.05,37.55,36.33,29.26,26.66, 23.36,20.67,11.74。

IIa-5: white solid, mp: 190-195°C; [α] _D ²⁵ 88.0 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (t, J=5.8 Hz, 1H), 8.97 (d, J=4.5Hz, 1H), 8.23–8.03 (m, 2H), 7.86–7.69 (m, 2H), 7.61 (ddd, J=8.4, 6.8, 1.3Hz, 1H), 7.46 –7.18(m,6H),6.79(dd,J=15.4,3.6 Hz,1H),6.07–5.90(m,2H),5.34–5.16(m,2H),4.64(d,J=15.9Hz,1H) ), 4.55–4.44 (m, 3H), 4.40–4.20 (m, 3H), 3.88 (dd, J=24.4, 13.1Hz, 1H), 3.62 (dq, J=16.6, 8.4, 7.5Hz, 1H), 2.83 (q, J=8.9Hz, 1H), 2.16 (t, J=11.9Hz, 1H), 1.91 (q, J=8.7, 7.1Hz, 3H), 1.04– 0.82 (m, 2H). ¹³ C NMR (101MHz,DMSO-d ₆ )δ164.49,150.58,148.04,145.20,138.57, 137.06,130.28,129.84,128.95,128.05,127.70,127.65,127.58,124.84,123.65,120.51,117.61,66.04,65.12,59.59,59.01, 57.38, 42.94, 37.55, 26.62, 23.37, 20.63, 11.74.

IIa-6: pale yellow solid, mp: 133-136°C; [α] _D ²⁵ 50.0 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 8.98 (d, J=4.5Hz, 1H), 8.12 (dd, J=27.2, 8.5Hz, 2H), 8.01–7.89 (m, 2H), 7.86–7.67 (m, 3H), 7.53 (t, J=7.7 Hz, 1H), 6.86 (dd, J=15.7, 3.4Hz, 1H), 6.18–5.86 (m, 2H), 5.38–5.12 (m, 2H), 4.90 (d, J=16.0Hz, 1H), 4.80 –4.59(m,1H),4.53 –4.07(m,3H),3.84(dt,J=76.3,11.7Hz,2H),2.86(q,J=8.8Hz,1H),2.16(q,J=11.9 Hz, 1H), 1.93 (d, J=8.4Hz, 3H), 1.07–0.92 (m, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ 165.02, 150.62, 148.07, 145.18, 137.02, 133.95, 132.93(t, J＝9.2Hz), 130.30, 129.91, 128.19–126.33(m), 124.87, 124.34, 123.75, 121.61, 120.57, 117.67, 66.12, 65.35, 59.60, 59.06, 25.32, 63.37. , 11.74. ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-59.52 (s, 3F).

IIa-7: white solid, mp: 172-176°C; [α] _D ²⁵ 35.6 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.67 (s, 1H), 8.99 ( d, J=4.5Hz, 1H), 8.27–8.05 (m, 2H), 7.85–7.65 (m, 4H), 7.57–7.41 (m, 2H), 7.31 (td, J=7.7, 1.7Hz, 1H) ,6.87(d,J＝3.2Hz,1H),6.17(t,J＝3.2Hz,1H),6.02(ddd,J＝17.2,10.1,6.8Hz,1H),5.38–5.15(m,2H), 4.88(d,J＝16.0Hz,1H),4.67(dd,J＝16.1,12.0Hz,1H),4.41(t,J＝10.5Hz,1H),4.28(t,J＝9.6Hz,2H), 3.92 (t, J=11.4Hz, 1H), 3.80–3.65 (m, 1H), 2.86 (q, J=8.7Hz, 1H), 2.33–2.14 (m, 1H), 1.95 (s, 3H), 1.10 –0.94(m,1H) ^.13C NMR(101MHz, _DMSO -d6)δ163.93,150.63,148.08,145.21,137.05,135.12,133.47,130.32,129.90,129.12,128.85,128.61,127.985,12 ,119.64,117.67,66.18,65.34,60.23,59.67,59.27,57.56,37.57,26.60,23.39,20.68,14.57,11.75.

IIa-8: milky white solid, mp: 129-134°C; [α] _D ²⁵ 66.4 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (d, J=3.6 Hz, 1H), 8.98 (d, J=4.5Hz, 1H), 8.24 (dt, J=8.8, 2.2Hz, 1H), 8.09 (dd, J=8.5, 1.2Hz, 1H), 7.81 (ddd, J=9.5 ,5.7,1.7Hz,2H),7.57(ddd,J＝8.4,6.8,1.4 Hz,1H),7.05(d,J＝2.2Hz,2H),6.80(dd,J＝15.9,3.6Hz,1H) ,6.37(t,J＝2.2Hz,1H),6.17-5.92(m,2H),5.77(s,1H),5.28(ddt,J＝14.9,3.1,1.4Hz,2H),4.95-4.80(m ,1H),4.69(d,J＝15.9Hz,1H),4.44-4.21(m,3H),4.00-3.87(m,1H),3.78(s,8H),3.38(s,2H),2.86( q, J=8.8Hz, 1H), 2.51 (p, J=1.8Hz, 1H), 2.22 (t, J=11.9Hz, 1H), 2.04–1.87 (m, 3H), 1.16–0.96 (m, 1H) ). ¹³ C NMR(101MHz,DMSO-d ₆ )δ163.32,161.12,150.66,148.06,145.17,139.90,137.05,130.38,129.90,127.40,124.83,123.72,120.63,117.65,98.43,96.92, 65.91,65.35,59.63 , 59.56, 57.54, 55.76, 55.42, 37.56, 26.60, 23.39, 20.63, 11.75.

IIa-9: white solid, mp: 172-177°C; [α] _D ²⁵ 35.6 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.45 (d, J=6.3 Hz, 1H), 8.97(d, J=4.5Hz, 1H), 8.25–7.97 (m, 2H), 7.88– 7.71 (m, 2H), 7.65–7.35 (m, 9H), 7.32–7.23 (m, 1H) ,6.74(dd,J＝15.0,3.2Hz,1H),6.04-5.70(m,2H),5.31-4.96(m,2H),4.68(d,J＝15.6Hz,1H),4.44-4.07(m ,3H),3.82(dt,J＝51.6,11.2Hz,2H),3.54–3.40(m,1H),2.77(q,J＝8.8Hz,1H),2.10(q,J＝12.1Hz,1H) , 1.97–1.71(m, 3H), 0.96–0.78(m, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ163.59, 150.60, 148.06, 145.18, 139.14, 138.26, 137.01, 133.52, 131.08, 130.28,129.89,129.19, 128.99,128.61,127.93,127.80,127.77,127.54,124.87,123.90,120.48,117.63,66.18,65.42,59.41,57.24,37.572.26.5

IIa-10: white solid, mp: 145-150°C; [α] _D ²⁵ 76.4 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 8.98 ( d, J=4.5Hz, 1H), 8.31 (dd, J=8.6, 3.3Hz, 1H), 8.22 (d, J=2.0Hz, 1H), 8.08 (dd, J=8.5, 1.2Hz, 1H), 7.86–7.73 (m, 3H), 7.71–7.64 (m, 2H), 7.59–7.48 (m, 5H), 7.46–7.37 (m, 1H), 6.81 (dd, J=15.9, 3.7Hz, 1H), 6.17(q,J＝5.8,4.4Hz,1H),6.02(ddd,J＝17.3,10.2,6.8Hz,1H),5.33-5.20(m,2H),5.00(d,J＝15.8Hz,1H) , 4.78(d,J＝15.6Hz,1H),4.54-4.19(m,3H),4.08-3.98(m,1H),3.83-3.65(m,1H),2.87(d,J＝8.4Hz,1H ), 2.29–2.14 (m, 1H), 1.92 (d, J=12.0Hz, 3H), 1.10–0.97 (m, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ170.79, 163.37, 150.67, 148.07 ,145.22,141.47,140.27, 138.87,137.04,130.36,130.21,129.83,129.56,128.30,127.43,127.09,124.85,123.83, 123.43,120.64,119.15,118.50,117.65,65.88,65.54,60.24,59.71,59.43,57.55 , 37.57, 26.62, 23.43, 21.25, 20.69, 14.56, 11.75.

IIa-11: white solid, mp: 216-222°C; [α] _D ²⁵ 64.5 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 8.99 ( d, J=4.5Hz, 1H), 8.27–8.03 (m, 2H), 7.88–7.74 (m, 2H), 7.51 (ddd, J=8.4, 6.8, 1.3Hz, 1H), 7.43 (d, J= 7.9Hz, 2H), 7.31 (dtd, J=21.0, 7.4, 1.6Hz, 2H), 6.88 (d, J=3.4Hz, 1H), 6.15–5.95 (m, 2H), 5.45–5.12 (m, 2H) ), 5.00–4.61 (m, 2H), 4.48–4.21 (m, 3H), 3.82 (dt, J=74.1, 11.5Hz, 2H), 3.31–3.13 (m, 1H), 2.87 (q, J=8.8 Hz, 1H), 2.17 (q, J=12.3Hz, 1H), 1.93 (d, J=13.1Hz, 3H), 1.16 (dd, J=21.0, 6.8Hz, 6H), 1.04 (dt, J=15.4 , 9.0Hz, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ164.15,150.65,148.07, 145.23,144.06,137.08,133.38,130.34,129.91,127.82,127.51,127.47,125.78,124 117.67, 66.21, 65.21, 59.67, 59.26, 57.42, 37.59, 27.74, 26.64, 23.97, 23.84, 23.39, 20.69, 11.75.

IIa-12: white solid, mp: 179-184°C; [α] _D ²⁵ 21.5 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (d, J=6.3 Hz, 1H), 8.99 (d, J=4.5Hz, 1H), 8.32–8.19 (m, 1H), 8.09 (dd, J=8.5, 1.2Hz, 1H), 7.86–7.73 (m, 2H), 7.62–7.46 (m, 2H), 7.30 (dddd, J=28.2, 13.7, 7.4, 1.8Hz, 3H), 6.87 (dd, J=16.1, 3.6Hz, 1H), 6.19–5.93 (m, 2H), 5.37–5.20 (m,2H), 4.93(d,J＝16.2Hz,1H),4.69(d,J＝16.3Hz,1H),4.49–4.32(m,2H),4.22(d,J＝9.8Hz,1H) ,3.95(t,J＝11.4Hz,1H),3.85-3.66(m,1H),2.86(q,J＝8.8Hz,1H),2.23-2.09(m,1H),1.97-1.82(m,3H) ), 1.39(d, J=1.5Hz, 10H), 0.99(d, J=12.1Hz, 1H). ¹³ C NMR (101 MHz, DMSO-d ₆ )δ164.81, 150.65, 148.09, 147.17, 145.30, 137.05, 134.52,131.91,130.31, 129.92,128.35,127.51,127.11,124.93,123.94,120.58,117.66,66.29,65.39,65.10,59.66,59.28,57.22,37.61,35.28,31.45,31.40,26.68,23.38,20.76,15.65, 11.74.

IIa-13: milky white solid, mp: 181-186°C; [α] _D ²⁵ 46.3 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (d, J=3.9 Hz, 1H), 8.98(d, J＝4.5Hz, 1H), 8.26(d, J＝8.3Hz, 1H), 8.09(dd, J＝8.5, 1.3Hz, 1H), 7.88–7.69(m, 4H), 7.62(ddd,J＝8.3,6.8,1.4Hz,1H),7.46(dd,J＝8.7,1.8Hz,2H),6.80(dd,J＝16.0,3.6Hz,1H),6.18–5.90(m, 2H), 5.28(ddd, J＝14.6, 3.1, 1.4Hz, 2H), 4.87(t, J＝14.3Hz, 1H), 4.69(d, J＝15.8Hz, 1H), 4.43–4.21(m, 3H ),3.95(d,J=11.1Hz,1H),3.73(q,J=9.3Hz,1H),2.86(q,J=8.8Hz,1H),2.51(p,J=1.8Hz,1H), 2.34–2.06(m, 1H), 1.94(t, J=8.2Hz, 3H), 1.29(s, 9H), 1.05(q, J=8.0, 6.4 Hz, 1H). ¹³ C NMR (101MHz, DMSO- d ₆ )δ170.79,162.91,150.63,148.05,147.51,145.24, 145.19,137.06,135.70,130.34,129.86,127.57,126.16,126.00,124.83,123.76,120.67,120.60,119.90,117.65,65.91,65.39,60.23,59.63 , 59.47, 57.51, 37.57, 34.64, 31.62, 26.61, 23.41, 21.25, 20.65, 14.57, 11.75.

IIa-14: pale yellow solid, mp: 263-267°C; [α] _D ²⁵ 26.5 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.80 (d, J=4.5Hz, 1H), 7.94 (d, J=9.2Hz, 1H), 7.77 (d, J=4.6Hz, 1H), 7.54–7.18 (m, 6H), 6.87 (d, J= 3.3Hz, 1H), 6.12–5.88 (m, 2H), 5.36–5.18 (m, 2H), 4.84 (d, J=16.8Hz, 1H), 4.72–4.39 (m, 3H), 4.23 (t, J =11.0Hz,1H),3.74(dt,J=31.7,11.1Hz,2H),3.42(s,3H),2.85(q,J=8.7Hz,1H),2.17–1.81(m,4H),1.37 (s, 9H), 0.91 (d, J=6.9Hz, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ165.16, 158.36, 147.72, 146.80, 144.21, 143.92, 137.02, 134.28, 131.80, 131.72, 128.23 ,127.41,126.92,126.15,122.78,120.82,117.66,101.91,66.59,64.05,60.79,59.52,57.31,56.13,37.73,35.28,31.44,26.83,23.32,20.96,11.

IIb-1: white solid, mp: 215-220°C; [α] _D ²⁵ -11.3 (c 0.20, CHCl ₃ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (s, 1H), 8.98 (d, J=4.5Hz, 1H), 8.21 (dd, J=8.6, 1.3Hz, 1H), 8.08 (dd, J=8.4, 1.2Hz, 1H), 7.84–7.68 (m, 2H), 7.61– 7.43(m, 2H), 7.30(dddd, J=26.6, 12.1, 7.3, 1.9Hz, 3H), 6.88(d, J=4.1Hz, 1H), 6.14(t, J=3.5Hz, 1H), 5.66 (ddd, J=17.4, 10.7, 5.6Hz, 1H), 5.34–4.98 (m, 2H), 4.96–4.64 (m, 2H), 4.47 (q, J=10.6, 9.9Hz, 2H), 4.30 (dt , J=12.6, 3.2Hz, 1H), 4.00 (dd, J=12.6, 10.2Hz, 1H), 3.90–3.77 (m, 1H), 2.88 (s, 1H), 2.22–1.89 (m, 4H), 1.38(s, 9H), 1.15–0.96(m, 1H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 164.97, 150.64, 148.05, 147.19, 145.38, 138.58, 134.53, 131.89, 130.35, 129.96, 128.33 ,127.48,127.46,127.14,124.72,123.69,120.49,116.17,65.96,64.51,60.40,59.31,56.21,37.29,35.27,31.40,25.76,25.26,21.55.

Example 17

Preparation of Asymmetric Fluorination Product Ib-1 of 4-Substituted Pyrazolones

Take 10mL single-neck reaction flask, add 0.0324g (0.1mmol) pyrazolone substrate Ia-1, NFSI 0.0346g (0.11mmol), and 0.0025g (0.005mmol) phase transfer catalyst IIa-1 respectively. Under 0 ℃, 2 mL of toluene was added, then 0.2 mL of 30 wt% K ₂ CO ₃ aqueous solution was added to the system, and after vigorously stirring the reaction for 10 min, TLC (thin layer chromatography) tracked the reaction to be basically complete. The product was isolated by column chromatography using a volume ratio of petroleum ether/ethyl acetate = 10:1. White solid, mp: 58-63°C; [α] _D ²⁵ 13.6 (c 0.41, CHCl ₃ ); 97% yield, 37% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.85–7.66 (m, 2H), 7.61–7.46(m, 2H), 7.35(dq, J=9.3, 2.6, 1.8Hz, 3H), 7.26–7.12(m, 2H), 7.08–6.87(m, 4H), 6.81–6.65( m, 2H), 3.61–3.21 (m, 2H). ¹³ C NMR (101MHz, Chloroform-d) δ166.88 (d, J=21.5Hz), 152.99 (d, J=13.9Hz), 135.78, 130.05, 128.82, 128.72, 128.29, 128.27, 128.01, 127.74, 127.29, 126.84, 125.54, 125.53, 124.80, 118.19, 95.27, 93.28, 40.05(d, J=26.0Hz). ¹⁹ F NMR-(376MHz) Chloroform 162.21 (s, 1F).HPLC conditions: Chiralcel AS-H column(250×4.6mm), hexane/i-PrOH=90/10, 1mL/min, 254nm, τR(major)＝5.83min, τR(minor)＝ 5.21min.

The implementation process of Examples 18 to 31 is the same as that of Example 17, but the phase transfer catalysts IIa-2 to IIa-15 are used instead of IIa-1. The results are shown in Table 2.

Table 2 Preparation of asymmetric fluorination product Ib-1 of pyrazolone using different catalysts

The implementation process of Examples 32 to 37 is the same as that of Example 28, but the temperatures listed in the table below are used instead of 0°C. The results are shown in Table 3.

Table 3 Preparation of pyrazolone fluorination product Ib-1 at different temperatures

The implementation process of Examples 38 to 47 is the same as that of Example 35, but the bases listed in the table below are used instead of 30 wt% K ₂ CO ₃ , and the results are shown in Table 4.

Table 4 Preparation of pyrazolone fluorination product Ib-1 using different bases

The implementation process of Examples 48 to 54 is the same as that of Example 43, but the solvents listed in the table below are used instead of toluene. The results are shown in Table 5.

Table 5 Preparation of pyrazolone hydroxylation product Ib-1 using different solvents

The implementation process of Examples 55 to 59 is the same as that of Example 43, but the 4-substituted pyrazolone concentrations listed in the following table are used instead of the original concentrations. The results are shown in Table 6.

Table 6 Preparation of hydroxylated product Ib-1 using different concentrations

The implementation process of Examples 60 to 63 is the same as that of Example 58, but the catalyst dosage listed in the following table is used instead of the original catalyst dosage. The results are shown in Table 7.

Table 7 Preparation of pyrazolone hydroxylation product Ib-1 using different catalyst amounts

The implementation process of Examples 64 to 67 is the same as that of Example 62, but the electrophilic fluorination reagents listed in the following table are used instead of the original electrophilic fluorination reagents. The results are shown in Table 8.

Table 8 Preparation of pyrazolone hydroxylation product Ib-1 using different fluorinated reagents

The implementation process of Examples 68 to 101 is the same as that of Example 17, but the 4-substituted pyrazolones Ia-2 to Ia-36 listed in the following table are used instead of the original substrate Ia-1. The results are shown in Table 9.

Table 9 Preparation of optically active fluorinated products Ib-2～Ib-35 using different 4-substituted pyrazolones

Example 68

Ib-2, white solid, mp: 140-144°C; [α] _D ²⁵ 95.1 (c 0.43, CHCl ₃ ); 95% yield, 94% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.94– 7.85 (m, 2H), 7.77–7.65 (m, 2H), 7.56–7.45 (m, 3H), 7.42–7.33 (m, 2H), 7.24–7.13 (m, 1H), 6.22 (t, J=2.3 Hz, 1H), 6.00 (d, J=2.3Hz, 2H), 3.68–3.37 (m, 8H). ¹³ C NMR (101MHz, Chloroform-d) δ 168.07 (d, J=21.3Hz), 160.50, 154.21(d, J＝13.7Hz), 136.96, 131.87(d, J＝12.1Hz), 131.11, 129.58(d, J＝1.7 Hz), 129.05, 128.87, 126.67, 126.66, 125.88, 119.17, 107.40, 100.87, 96.15, 94.17, 55.03, 41.36 (d, J=26.3 Hz). ¹⁹ F NMR (376 MHz, Chloroform-d) δ-161.82 (s, 1F). HPLC conditions: Chiralcel AS-H column (250×4.6 mm), hexane/i-PrOH=95/5, 1mL/min, 254nm, τR(major)=7.54min, τR(minor)=8.28min.

Example 69

Ib-3, pale yellow solid, mp: 102-106°C; [α] _D ²⁵ 55.6 (c 0.54, CHCl ₃ ); 98% yield, 87% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.94 –7.82 (m, 2H), 7.72–7.60 (m, 2H), 7.59–7.44 (m, 3H), 7.38 (dd, J=8.7, 7.5Hz, 4H), 7.26–7.16 (m, 2H), 7.02 (d, J=8.0Hz, 2H), 3.73–3.48 (m, 2H). ¹³ C NMR (101MHz, Chloroform-d) δ 166.50 (d, J=21.4 Hz), 152.86 (d, J=13.7 Hz) a J＝26.6Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-62.76(s,3F),-162.96(s,1F).HPLC conditions:Chiralcel OJ-Hcolumn(250×4.6mm),hexane/i -PrOH=95/5, 1mL/min, 254nm, τR(major)=8.32min, τR(minor)=7.76min.

Example 70

Ib-4, pale yellow solid, mp: 102-106°C; [α] _D ²⁵ 55.6 (c 0.54, CHCl ₃ ); 98% yield, 87% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.93 –7.83(m,2H),7.80-7.66(m,2H),7.61-7.48(m,3H),7.45-7.33(m,2H),7.25-7.17(m,1H),6.61(tt,J= 8.8, 2.3Hz, 1H), 6.52–6.30 (m, 2H), 3.70–3.37 (m, 2H). ¹³ C NMR (101MHz, Chloroform-d) δ 167.41 (d, J=21.3Hz), 163.86 ( d, J＝12.7Hz), 161.38(d, J＝12.8Hz), 153.87(d, J＝13.7Hz), 136.72, 133.83, 131.46, 129.26, 128.99, 126.60, 126.58, 126.15, 119.18, 113.02(d, J=25.6Hz), 103.69(t, J=25.1Hz), 95.55, 93.55, 40.55(d, J=27.5Hz). ¹⁹ F NMR (376MHz, Chloroform-d) δ -109.16(s, 2F), - 162.68(s, 1F).HPLC conditions: Chiralcel OJ-H column(250×4.6mm), hexane/i-PrOH=95/5, 1mL/min, 254nm, τR(major)=8.32min, τR(minor) =7.76min.

Example 71

Ib-5, pale yellow solid, mp: 117-121°C; [α] _D ²⁵ 27.6 (c 0.51, CHCl ₃ ); 97% yield, 80% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 8.02 –7.82(m,4H),7.78–7.65(m,2H),7.62–7.46(m,3H),7.43–7.31(m,2H),7.25–7.17(m,1H),7.14–6.94(m, 2H), 3.81–3.55(m, 2H). ¹³ C NMR(101MHz, Chloroform-d)δ167.24(d,J=21.3Hz),153.70(d,J=13.8Hz), 147.62,137.68,137.57, 136.61, 131.57, 131.01, 129.32, 129.01, 128.93, 128.92, 126.58, 126.56, 126.22, 123.52, 118.98, 95.55, 93.55, 40.73(d, J＝27.2Hz). ¹⁹ F NMR-(376MHz) Chloroform 162.65(s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝10.02min,τR(minor) = 12.02 min.

Example 72

Ib-6, pale yellow colloid; [α] _D ²⁵ 110.7 (c 0.58, CHCl ₃ ); 95% yield, 84% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.90–7.80 (m, 2H) ,7.71–7.60(m,2H),7.57–7.46(m,3H),7.44–7.30(m,3H),7.21(ddt,J=8.6,7.2,1.2Hz,2H),7.15–7.04(m, 2H), 3.72–3.47(m, 2H). ¹³ C NMR(101MHz, Chloroform-d)δ167.58(d,J=21.5Hz),153.93(d,J=13.7Hz), 136.65,133.31,131.39, 131.29–130.81(m), 129.21, 129.16, 129.14, 128.92, 128.90, 126.88 (q, J=3.8Hz), 126.63, 126.61, 126.09, 125.23–124.39(m), 95.91, 93.91, 40.81(d, J=3.8Hz) 26.8 Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-62.90(s,3F),-163.34(s,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i- PrOH=95/5, 1mL/min, 254nm, τR(major)=10.40min, τR(minor)=8.67min.

Example 73

Ib-7, white solid, mp: 85-89°C; [α] _D ²⁵ 46.5 (c 0.42, CHCl ₃ ); 96% yield, 83% ee. ¹ HNMR (400 MHz, Chloroform-d) δ 7.81 (dq , J=6.9, 1.2Hz, 2H), 7.72–7.62 (m, 3H), 7.59– 7.44 (m, 3H), 7.43–7.29 (m, 4H), 7.25–7.18 (m, 1H), 3.82–3.52 (m, 2H). ¹³ C NMR (101 MHz, Chloroform-d) δ 167.19 (d, J = 21.4 Hz), 153.71 (d, J = 13.5 Hz), 136.46, 132.86 (d, J = 10.6 Hz) ,131.73(q,J＝33.6Hz),131.65,130.33,129.33,128.98,126.60,126.58,126.28,122.78(q,J＝272.8Hz),122.04,122.00,121.96,95.41,93.40,40.61(d =27.2Hz). ¹⁹ FNMR(376MHz, Chloroform-d)δ-63.10(s,6F),-164.38(s,1F).HPLC conditions:ChiralcelAD-H column(250×4.6mm),hexane/i-PrOH =98/2, 1mL/min, 254nm, τR(major)=22.00min, τR(minor)=18.38min.

Example 74

Ib-8, pale yellow solid, mp: 165-169°C; [α] _D ²⁵ 56.7 (c 0.72, CHCl ₃ ); 96% yield, 87% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.88 –7.73 (m, 4H), 7.48–7.30 (m, 5H), 7.23–7.17 (m, 1H), 3.57 (tt, J=15.2, 1.8Hz, 1H), 3.29 (ddt, J=26.9, 15.1, 1.6Hz, 1H). ¹³ C NMR (101 MHz, Chloroform-d) δ 165.72 (d, J=22.6Hz), 153.29 (d, J=13.7Hz), 153.22, 146.02, 143.59, 143.55, 141.35, 138.81 , 137.60, 135.99, 130.45, 128.06, 127.98, 125.60, 125.58, 125.10, 117.98, 104.31(t, J=18.1Hz), 92.43, 90.40, 28.68, 27.29(d, J=26.7Hz). ¹⁹ F NMR(376MHz) ,Chloroform-d)δ-139.19–-139.75(m,2F),-153.43(t,J=20.8Hz,1F),-161.83(dd,J=21.0,14.2Hz,2F),-170.79(t, J=10.5Hz, 1F). HPLC conditions: Chiralcel AD-Hcolumn (250×4.6mm), hexane/i-PrOH=90/10, 1mL/min, 254nm, τR(major)=5.04 min, τR(minor) =5.54min.

Example 75

Ib-9, pale yellow colloid; [α] _D ²⁵ 48.2 (c 0.41, CHCl ₃ ); 99% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95–7.86 (m, 2H) ,7.74-7.62(m,2H),7.57-7.46(m,3H),7.40-7.33(m,2H),7.20(t,J＝7.4Hz,1H),7.00(t,J＝7.9Hz,1H ), 6.67(ddd, J=8.3, 2.6, 0.9Hz, 1H), 6.49(dt, J=7.5, 1.2Hz, 1H), 6.38(t, J=2.1Hz, 1H), 3.69–3.51(m, 2H), 3.49(s, 3H). ¹³ C NMR(101MHz, Chloroform-d) δ168.05(d, J=21.5Hz), 159.39, 154.19(d, J=13.8Hz), 136.93, 131.32, 131.20, ^{131.14,129.53,129.52,129.42,129.10,128.88,126.69,126.68} , 125.92,122.23,119.30,114.59,114.42,96.28,94.29,54.92,41.21(d,J=26.3Hz). d) δ-162.10(s, 1F).HPLC conditions: Chiralcel OJ-H column(250 × 4.6mm), hexane/i-PrOH=80/20, 1mL/min, 254nm, τR(major)=8.86min, τR(minor) = 13.25 min.

Example 76

Ib-10, white solid, mp: 86-89°C; [α] _D ²⁵ 56.7 (c 0.42, CHCl ₃ ); 98% yield, 92% ee. ¹ HNMR (400 MHz, Chloroform-d) δ 7.72 (dq , J=8.4, 1.5Hz, 4H), 7.40–7.24 (m, 5H), 7.17– 7.06 (m, 1H), 6.89–6.63 (m, 2H), 6.38 (dd, J=9.0, 4.4Hz, 1H ), 3.72–3.27(m, 2H), 3.09(s, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ167.19(d, J=21.8Hz), 155.19–153.34(m), 152.72, 152.70 ,136.12,128.70,128.68,127.88,127.44,125.45,125.43,124.73,119.58,117.97,117.64(d,J＝23.6Hz),114.14(d,J＝22.7Hz),109.48(d,J＝8.4Hz) , 94.88, 92.89, 53.74, 34.19(d, J=27.1Hz). ¹⁹ F NMR(376MHz, Chloroform-d) δ-124.15(s, 1F), -164.47(s, 1F).HPLC conditions: Chiralcel OJ- H column (250×4.6mm), hexane/i-PrOH=95/5, 1mL/min, 254nm, τR(major)=17.41min, τR(minor)=16.05min.

Example 77

Ib-11, colorless colloid; [α] _D ²⁵ 112.3 (c 0.42, CHCl ₃ ); 99% yield, 90% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J=8.5 Hz ,1H),7.75–7.62(m,4H),7.59–7.50(m,2H),7.47–7.38(m,1H),7.39–7.29(m,5H),7.25–7.21(m,1H),7.21 -7.11(m,3H),4.10-3.95(m,2H) ^.13C NMR(101MHz,Chloroform-d)δ168.52(d,J=21.8Hz),154.84(d,J=13.9Hz),136.85 ,133.63,132.02,130.92,129.68,129.66,129.20,128.82,128.76,128.53,126.76,126.67,126.65,125.87,125.86,125.60,124.82,123.64,119.24,96.54,94.55,37.30(d,J＝ 26.4Hz) . ¹⁹ F NMR(376MHz,Chloroform-d)δ-163.17(s,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm , τR(major)=15.19min, τR(minor)=12.76min.

Example 78

Ib-12, white solid, mp: 103-107°C; [α] _D ²⁵ 53.8 (c 0.62, CHCl ₃ ); 98% yield, 90% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.82– 7.70 (m, 2H), 7.67–7.58 (m, 2H), 7.51–7.40 (m, 3H), 7.39–7.26 (m, 3H), 7.18–7.12 (m, 1H), 6.90 (d, J=1.7 Hz, 2H), 3.53–3.25(m, 2H). ¹³ CNMR(101MHz, Chloroform-d)δ166.40(d,J=21.5Hz),152.85(d,J=13.6Hz), 135.52,132.91,132.81 , 132.68, 130.78, 130.46, 128.22, 128.07, 128.06, 127.96, 125.60, 125.58, 125.23, 121.68, 118.42, 94.52, 92.51, 39.14(d, J=27.0Hz). ¹⁹ F NMR(376MHz, δChloroform) -163.81(s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝4.51min,τR(minor ) = 5.43 min.

Example 79

Ib-13, tan solid, mp: 104-108°C; [α] _D ²⁵ 48.2 (c 0.40, CHCl ₃ ); 98% yield, 90% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.87 –7.77(m,2H),7.65-7.54(m,2H),7.48-7.37(m,3H),7.33-7.23(m,2H),7.14-7.04(m,1H),6.81(d,J= 7.8Hz, 2H), 6.74–6.64 (m, 2H), 3.68–3.30 (m, 2H), 2.10 (s, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 168.14 (d, J = 21.5 Hz), 154.24(d, J＝13.9Hz), 137.63, 136.96, 131.13, 129.80, 129.49, 129.14, 129.11, 128.86, 126.71, 126.69, 126.60, 125.90, 119.39, 96.39, 9.26.0, 4 Hz), 21.07. ¹⁹ FNMR(376MHz, Chloroform-d)δ-161.89(s, 1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/ min, 254nm, τR(major)=9.65min, τR(minor)=8.49min.

Example 80

Ib-14, pale yellow solid, mp: 80-84°C; [α] _D ²⁵ 27.4 (c 0.38, CHCl ₃ ); 99% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.98 (tdd, J=6.3, 2.9, 1.1Hz, 4H), 7.57–7.36 (m, 5H), 7.30–7.20 (m, 1H), 1.88 (d, J=22.6Hz, 3H). ¹³ C NMR (101MHz) ,Chloroform-d)δ168.65(d,J＝22.0Hz),155.61(d,J＝14.5Hz),137.42,131.26,129.05,129.01,128.54,128.53,126.69,126.67,125.77,118.80,93.70,91.7 ,29.70,21.42(d,J＝26.5Hz). ¹⁹ F NMR(376MHz,Chloroform-d)δ-163.74(s,1H).HPLC conditions:Chiralcel AD-H column(250×4.6 mm),hexane/i -PrOH=98/2, 0.8mL/min, 254nm, τR(major)=11.02min, τR(minor)=8.59min.

Example 81

Ib-15, colorless oil; [α] _D ²⁵ 64.5 (c 0.31, CHCl ₃ ); 92% yield, 94% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 8.03–7.82 (m, 4H ), 7.56–7.38 (m, 5H), 7.24 (d, J=7.5Hz, 1H), 5.54–5.32 (m, 1H), 5.22–4.92 (m, 2H), 3.18–2.89 (m, 2H). ¹³ C NMR(101MHz, Chloroform-d)δ167.90(d,J=21.7Hz),154.26(d,J=13.9Hz),137.23,131.23,129.06,128.99,128.94,126.63,126.62,126.37,126.26, 125.82, 122.71, 118.94, 95.41, 93.43, 39.16 (d, J=26.1 Hz). ¹⁹ F NMR (376 MHz, Chloroform-d) δ-164.30 (s, 1F). HPLC conditions: ChiralcelAD-H column (250×4.6 mm), hexane/i-PrOH=90/10, 1mL/min, 254nm, τR(major)=5.54min, τR(minor)=4.95min.

Example 82

Ib-16, colorless oil; [α] _D ²⁵ 57.3 (c 0.25, CHCl ₃ ); 94% yield, 89% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 (ddt, J=15.4 , 7.9, 1.2Hz, 4H), 7.58–7.39 (m, 5H), 7.30–7.26 (m, 1H), 3.27 (ddd, J=15.8, 8.1, 2.8Hz, 1H), 3.12 (ddd, J=15.8 , 7.5, 2.8Hz, 1H), 1.93 (t, J=2.7Hz, 1H). ¹³ C NMR (101MHz, Chloroform-d) δ165.82 (d, J=21.0Hz), 152.35 (d, J=13.4 Hz), 136.08, 130.33, 128.07, 127.99, 127.56, 127.54, 125.56, 125.54, 124.94, 118.04, 92.99, 91.00, 72.12(d, J=19.0Hz), 71.90(d, J=2.6Hz), 24.30(d , J＝34.1Hz). ¹⁹ F NMR (376MHz, Chloroform-d)δ-164.40(s, 1F).HPLC conditions: Chiralcel AD-Hcolumn(250 ×4.6mm), hexane/i-PrOH＝80/20, 1mL/min, 254nm, τR(major)=5.85min, τR(minor)=5.19min.

Example 83

Ib-17, colorless oil; [α] _D ²⁵ 29.6 (c 0.21, CHCl ₃ ); 95% yield, 72% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.67–7.59 (m, 2H ), 7.40–7.30 (m, 2H), 7.29–7.23 (m, 3H), 7.21– 7.12 (m, 3H), 3.65–3.10 (m, 2H), 2.14 (d, J=1.6Hz, 3H). ¹³ C NMR(101MHz, Chloroform-d)δ136.97,130.65,130.55,129.76,128.87,128.77,128.06,125.65,118.96, 95.52,93.56,13.83. ¹³ C NMR(101MHz,Chloroform-d)δ167. J=21.0 Hz), 157.01 (d, J=16.4 Hz), 39.41 (d, J=26.1 Hz). ¹⁹ F NMR (376 MHz, Chloroform-d) δ-167.08 (s, 1F). HPLC conditions: Chiralcel AD- H column (250×4.6mm), hexane/i-PrOH=99/1, 1mL/min, 254nm, τR(major)＝＝16.00min, τR(minor)＝13.90min.

Example 84

Ib-18, white solid, mp: 131-135°C; [α] _D ²⁵ 79.5 (c 0.41, CHCl ₃ ); 99% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.76– 7.65(m,3H),7.59(dt,J=9.6,2.1Hz,1H),7.48(td,J=8.1,5.7Hz,1H),7.39(dd,J=8.6,7.4Hz,2H),7.25 –7.18(m, 2H), 6.23(t, J=2.3Hz, 1H), 6.01(d, J=2.3Hz, 2H), 3.71–3.32(m, 8H). ¹³ C NMR (101MHz, Chloroform-d) ) δ167.96(d,J＝21.3Hz),164.16,161.70,160.57,153.18(dd,J＝13.9,3.2Hz),136.78,131.72,131.60,131.56,131.47,130.82,130.74,1228.50,126.0 , 122.48, 122.45, 119.17, 118.14 (d, J = 21.3 Hz), 114.50–112.27 (m), 107.43, 100.77, 95.88, 93.89, 55.06, 41.33 (d, J = 26.1 Hz). ¹⁹ F NMR (376 MHz, Chloroform-d)δ-110.99(s,1F),-162.34(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH=90/10,1mL/min, 254nm, τR(major)==6.84min, τR(minor)=7.63min.

Example 85

Ib-19, white solid, mp: 122-126°C; [α] _D ²⁵ 64.3 (c 0.40, CHCl ₃ ); 97% yield, 86% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.89– 7.78 (m, 2H), 7.77–7.62 (m, 2H), 7.54–7.43 (m, 2H), 7.43–7.33 (m, 2H), 7.25–7.15 (m, 1H), 6.23 (t, J=2.3 Hz, 1H), 6.00 (d, J=2.3Hz, 2H), 3.65–3.33 (m, 8H). ¹³ C NMR (101MHz, Chloroform-d) δ 167.96 (d, J=21.4Hz), 160.60, 153.32(d, J＝14.0Hz), 137.26, 136.85, 131.80, 131.69, 129.40, 128.94, 128.04, 128.02, 127.92, 127.90, 126.01, 119.19, 107.52, 100.68, 95.941.94 26.2Hz) ^.19F NMR(376MHz,Chloroform-d)δ-162.48(s,1F).HPLC conditions:ChiralcelAD-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/min ,254nm,τR(major)==21.46min,τR(minor)=17.56min.

Example 86

Ib-20, pale yellow solid, mp: 131-135°C; [α] _D ²⁵ 27.5 (c 0.57, CHCl ₃ ); 98% yield, 86% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.80 –7.60(m,2H),7.43(ddd,J=8.2,1.8,1.0Hz,1H),7.41–7.31(m,3H),7.24–7.13(m,1H),6.92(d,J=8.1Hz ,1H),6.23(t,J＝2.3Hz,1H),6.11-5.94(m,4H),3.63-3.35(m,8H) ^.13C NMR(101MHz,Chloroform-d)δ167.90(d, J＝21.6Hz),160.49,153.86,153.72,150.13,148.43,136.96,132.02,131.90,128.83,125.78,123.71,123.69,122.05,122.02,119.10,108.65,107.53,106.24,101.71,100.61,96.25,94.27, 55.09, 41.61(d, J＝26.3Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-161.64(s, 1F).HPLC conditions:Chiralcel AS-H column(250×4.6mm),hexane/i- PrOH=80/20, 1mL/min, 254nm, τR(major)==8.45min, τR(minor)=10.87min.

Example 87

Ib-21, pale yellow solid, mp: 78-81°C; [α] _D ²⁵ 43.2 (c 0.40, CHCl ₃ ); 93% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J=8.1Hz, 2H), 7.73 (dd, J=8.4, 6.9Hz, 4H), 7.46–7.35 (m, 2H), 7.23 (d, J=7.5Hz, 1H), 6.23 (t, J=2.3Hz, 1H), 5.98 (d, J=2.3Hz, 2H), 3.57–3.32 (m, 8H). ¹³ C NMR (101MHz, Chloroform-d) δ 167.98 (d, J=21.1Hz) , 160.62, 152.98(d, J＝14.1Hz), 136.73, 132.47(q, J＝32.8Hz), 128.98, 126.92, 126.91, 126.22, 125.97, 125.93, 123.67(q, J＝1651.3, 817.3Hz), 119.22 , 107.53, 100.64, 95.78, 93.79, 55.04, 41.29(d, J=26.0Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-62.99(s,3F), -162.75(s,1F).HPLC conditions : Chiralcel AD-H column (250×4.6mm), hexane/i-PrOH=90/10, 1mL/min, 254nm, τR(major)＝＝7.44min, τR(minor)＝6.46min.

Example 88

Ib-22, white colloid; [α] _D ²⁵ 52.5 (c 0.42, CHCl ₃ ); 97% yield, 90% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.82 (d, J=8.0 Hz, 2H), 7.78–7.66 (m, 2H), 7.45–7.30 (m, 4H), 7.24– 7.09 (m, 1H), 6.22 (t, J=2.3Hz, 1H), 6.01 (d, J=2.2Hz) , 2H), 3.46(s, 8H), 3.07–2.84(m, 1H), 1.30(dd, J=6.9, 1.1Hz, 6H). ¹³ C NMR(101MHz, Chloroform-d)δ168.05(d, J=21.4Hz),160.44,154.31(d,J=13.8Hz),152.41,137.02,132.07,131.95,128.84,127.18,127.12,126.79,126.78,125.78,119.16,107.39,4.2.93,96. 41.43(d, J＝26.2Hz), 34.21, 23.75, 23.74. ¹⁹ F NMR(376MHz, Chloroform-d)δ-161.86(s, 1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane /i-PrOH=80/20, 1 mL/min, 254 nm, τR(major)==5.80min, τR(minor)=4.77min.

Example 89

Ib-23, white solid, mp: 140-144°C; [α] _D ²⁵ 37.2 (c 0.38, CHCl ₃ ); 98% yield, 90% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 8.04– 7.89 (m, 2H), 7.79–7.69 (m, 4H), 7.69–7.61 (m, 2H), 7.54–7.46 (m, 2H), 7.44–7.34 (m, 3H), 7.25–7.19 (m, 1H) ), 6.23(t, J=2.3Hz, 1H), 6.05(d, J=2.3Hz, 2H), 3.69–3.49(m, 2H), 3.47(s, 6H). ¹³ C NMR(101MHz, Chloroform- d) δ168.12(d, J＝21.3Hz), 160.55, 154.03(d, J＝14.0Hz), 143.75, 139.90, 137.01, 131.97(d, J＝11.8Hz), 129.05, 128.92, 128.44, 128.43, 128.18,127.64,127.18, 127.16,127.12,125.94,119.23,107.53,100.85,96.22,94.24,55.09,41.52(d,J=26.2Hz). ¹⁹ FNMR(376MHz,Chloroform-d)δ-162.05( ).HPLC conditions: Chiralcel AD-H column (250×4.6mm), hexane/i-PrOH=80/20, 1mL/min, 254nm, τR(major)==11.16 min, τR(minor)=8.91min.

Example 90

Ib-24, white solid, mp: 145-150°C; [α] _D ²⁵ 38.1 (c 0.31, CHCl ₃ ); 93% yield, 89% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.95 ( d, J=8.3Hz, 2H), 7.82–7.64 (m, 4H), 7.46–7.35 (m, 2H), 7.31–7.18 (m, 1H), 6.23 (t, J=2.3Hz, 1H), 5.97 (d, J=2.3Hz, 2H), 3.66– 3.37 (m, 8H). ¹³ C NMR (101MHz, Chloroform-d) δ 167.96 (d, J=21.2Hz), 160.69, 152.52 (d, J= 14.1Hz), 136.63, 133.51, 133.49, 132.71, 131.58, 131.47, 129.04, 127.01, 127.00, 126.39, 119.23, 118.15, 114.22, 107.59, 100.52, 95.64, 95.2.65, 4 ¹⁹ F NMR(376MHz,Chloroform-d)δ-163.05(s,1F).HPLC conditions:ChiralcelAD-H column(250×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR (major)=10.41min, τR(minor)=13.74min.

Example 91

Ib-25, white solid, mp: 132-135°C; [α] _D ²⁵ 42.3 (c 0.40, CHCl ₃ ); 98% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.73 ( d, J=8.0Hz, 2H), 7.68–7.57 (m, 2H), 7.35–7.26 (m, 2H), 7.23 (d, J=8.0Hz, 2H), 7.16–7.07 (m, 1H), 6.14 (t, J=2.3Hz, 1H), 5.94 (d, J=2.3Hz, 2H), 3.55–3.32 (m, 8H), 2.36 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ168. 07(d, J＝21.5Hz), 160.49, 154.33(d, J＝13.9Hz), 141.63, 137.03, 132.06, 131.93, 129.79, 128.86, 126.81, 126.66, 126.64, 125.82, 119.20, 107.3.9, 10 94.32, 55.08, 41.46(d, J＝26.2Hz), 21.68. ¹⁹ F NMR(376MHz, Chloroform-d)δ-161.91(s, 1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane /i-PrOH=98/2, 1mL/min, 254nm, τR(major)==18.71min, τR(minor)=14.22min.

Example 92

Ib-26, white solid, mp: 114-119°C; [α] _D ²⁵ 51.2 (c 0.41, CHCl ₃ ); 99% yield, 95% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.90 ( d, J=1.9Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 7.68–7.60 (m, 2H), 7.59–7.50 (m, 1H), 7.30 (dt, J=10.3, 7.7Hz) ,3H),7.16(q,J＝7.4,6.2Hz,1H),6.16(t,J＝2.3Hz,1H),5.93(d,J＝2.3Hz,2H),3.55–3.31(m,8H) . ¹³ C NMR (101 MHz, Chloroform-d) δ 166.91 (d, J=21.3 Hz), 159.55, 151.92 (d, J=13.8 Hz), 135.74, 132.91, 131.02–130.16 (m), 129.50, 127.90 ,125.06,124.16(d,J＝2.0Hz),122.18,118.15,106.44,99.85,94.80,92.82,54.04,40.28(d,J＝26.0Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-162.59 (s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝6.60min,τR(minor)＝ 7.38 min.

Example 93

Ib-27, white solid, mp: 148-152°C; [α] _D ²⁵ 21.2 (c 0.40, CHCl ₃ ); 98% yield, 96% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.79– 7.62 (m, 2H), 7.50 (dt, J=8.6, 1.5Hz, 1H), 7.43–7.32 (m, 3H), 7.25–7.15 (m, 1H), 6.97 (d, J=8.4Hz, 1H) ,6.23(t,J=2.3Hz,1H),6.04(d,J=2.3Hz,2H),3.98(s,3H),3.94(s,3H), ^3.62–3.39 (m, ^8H ). C NMR(101MHz, CDCl ₃ )δ168.00(d,J=21.4Hz),160.51,154.12(d,J=13.8Hz),151.71,149.52,136.99,132.06(d,J=12.1Hz),128.85, 125.86, ^122.47 , 120.80, 120.77, 119.32, 110.86, 108.54, 107.59, 100.67, 96.35, 94.37, 56.06, 55.09, 41.78. J＝26.2Hz).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝9.20min,τR(minor)＝ 10.84 min.

Example 94

Ib-28, white colloid; [α] _D ²⁵ 17.8 (c 0.40, CHCl ₃ ); 98% yield, 94% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.76–7.64 (m, 3H), 7.59(dt,J=9.7,2.1Hz,1H),7.48(td,J=8.1,5.7Hz,1H),7.43-7.33(m,2H),7.25-7.17(m,2H),6.23(t, J=2.3Hz, 1H), 6.01 (d, J=2.3Hz, 2H), 3.63–3.39 (m, 8H). ¹³ C NMR (101MHz, Chloroform-d) δ 167.99 (d, J=21.2Hz) ,164.19,161.73,160.60,153.20(d,J=10.9Hz),136.81,132.33–131.31(m),130.81(d,J=8.1Hz),128.95,126.10,122.53,122.51,122.49,119.20,118 d, J=21.3Hz), 113.40 (d, J=23.3Hz), 107.46, 100.80, 95.90, 93.92, 55.08, 41.36 (d, J=26.2Hz). ¹⁹ F NMR (376MHz, Chloroform-d)δ- 111.00(s,1F),-162.32(s,1F).HPLC conditions:ChiralcelAD-H column (250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝ 6.62min,τR(minor)=7.34min.

Example 95

Ib-29, white solid, mp: 63-67°C; [α] _D ²⁵ 39.5 (c 0.40, CHCl ₃ ); 98% yield, 80% ee. ¹ HNMR (400 MHz, Chloroform-d) δ 8.20-8.06 (m, 2H), 7.95 (s, 1H), 7.83–7.68 (m, 2H), 7.51–7.31 (m, 2H), 7.34–7.26 (m, 1H), 6.23 (t, J=2.3Hz, 1H) ), 5.99(d, J＝2.3Hz, 2H), 3.61–3.40(m, 8H). ¹³ C NMR(101MHz, Chloroform-d)δ167.89(d, J＝21.2Hz), 160.78, 152.06(d , J=14.4Hz), 136.58, 132.48(q, J=33.9Hz), 131.91–131.45(m), 129.12, 126.54, 126.35, 124.17, 123.99, 107.78, 100.45, 95.45, 93.46, 55.04, 41.45(d J＝25.6Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-62.99(s,6F),-164.91(s,1F).HPLC conditions: ChiralcelAS-H column(250×4.6mm),hexane/i -PrOH=95/5, 1 mL/min, 254 nm, τR(major)=4.38min, τR(minor)=3.82min.

Example 96

Ib-30, brown colloid; [α] _D ²⁵ 19.3 (c 0.40, CHCl ₃ ); 98% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 8.00–7.87 (m, 4H), 7.67–7.60 (m, 2H), 7.57–7.49 (m, 3H), 6.21 (t, J=2.3Hz, 1H), 5.98 (d, J=2.3Hz, 2H), 3.61–3.35 (m, 8H) . ¹³ C NMR (101MHz, Chloroform-d) δ168.33 (d, J=21.6Hz), 160.56, 154.82 (d, J=13.9Hz), 139.69, 131.52, 131.49, 129.17, 128.23-126.91 (m), 126.80, 126.78, 126.15, 126.12, 118.45, 107.42, 100.75, 96.18, 94.19, 55.05, 41.37(d, J=26.1Hz). ¹⁹ F NMR(376MHz, Chloroform-d)δ-62.25(s, 3F),- 161.37(s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH=80/20,1mL/min,254nm,τR(major)=6.06min,τR(minor) =6.40min.

Example 97

Ib-31, white colloid; [α] _D ²⁵ 57.1 (c 0.40, CHCl ₃ ); 92% yield, 83% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.90–7.72 (m, 2H), 7.57–7.33 (m, 3H), 6.25 (t, J=2.3Hz, 1H), 5.96 (d, J=2.2Hz, 2H), 3.56–3.41 (m, 8H). ¹³ C NMR (101MHz, Chloroform- d) δ167.53 (d, J=21.6Hz), 159.72, 154.90 (d, J=14.1Hz), 144.05 (dd, J=12.0, 4.1Hz), 142.66–140.89 (m), 141.46–138.89 (m ),138.50–137.16(m),136.44–134.59(m),130.55,128.21,128.08,128.07,125.71,125.70,106.75,99.60,93.51,91.53,54.06,39.96(d,J= ^26.0Hz ). NMR(376MHz, Chloroform-d)δ-142.54–143.00(m,2F),-151.62–152.05(m,1F),-160.88(s,1F),-160.92–161.16(m,2F).HPLC conditions: Chiralcel AD-H column (250×4.6mm), hexane/i-PrOH=90/10, 1mL/min, 254nm, τR(major)=5.46min, τR(minor)=6.08min.

Example 98

Ib-32, brown oil; [α] _D ²⁵ 43.2 (c 0.40, CHCl ₃ ); 97% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.88–7.71 (m, 4H) ,7.58–7.37(m,5H),7.10–6.94(m,3H),6.86–6.71(m,2H),3.64–3.39(m,2H). ^13C NMR(101MHz,Chloroform-d)δ167.21 (d, J=21.7 Hz), 153.70 (d, J=14.0 Hz), 138.56, 130.47, 128.81, 128.62, 128.50, 128.17, 128.04 (d, J=1.8 Hz), 127.43, 127.04, 125.75 (d, J = 1.8Hz), 125.07 (q, J = 3.8 Hz), 117.49, 95.38, 93.38, 40.16 (d, J = 26.0 Hz). ¹⁹ F NMR (376 MHz, Chloroform-d) δ-62.27 (s, 3F), -162.06(s, 1F). HPLC conditions: Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH=99/1, 1mL/min, 254nm, τR(major)=9.62min, τR(minor ) = 7.28 min.

Example 99

Ib-33, white solid; mp: 73-76°C; [α] _D ²⁵ 58.1 (c 0.40, CHCl ₃ ); 97% yield, 90% ee. ¹ HNMR (400 MHz, Chloroform-d) δ 8.01-7.76 (m, 4H), 7.54–7.33 (m, 5H), 6.13 (t, J=2.3 Hz, 1H), 5.92 (d, J=2.3 Hz, 2H), 3.55–3.42 (m, 2H), 3.40 ( s, 6H). ¹³ C NMR (101MHz, CDCl ₃ )δ168.23(d, J=21.6Hz), 160.59, 154.76(d, J=14.1Hz), 137.40, 131.69, 131.56, 131.48, 131.21, 129.54, 129.24,129.18,126.82,126.80,123.02–121.87(m),121.84,115.94–115.33(m),107.44,100.78,96.26,94.27,55.05,41.43(d,J=26.2Hz). ¹⁹ MHz F NMR(36 MHz ,Chloroform-d)δ-62.71(s,3F),-161.76(s,1F).HPLC conditions:Chiralcel AD-Hcolumn(250×4.6mm),hexane/i-PrOH＝93/7,1mL/min, 254nm, τR(major)=5.27min, τR(minor)=5.89min.

Example 100

Ib-34, brown oil; [α] _D ²⁵ 31.2 (c 0.40, CHCl ₃ ); 97% yield, 92% ee. ¹ H NMR (400 MHz, Chloroform-d) δ 7.97–7.82 (m, 2H) ,7.57–7.44(m,5H),7.32–7.20(m,1H),7.03(ddt,J=7.5,1.7,0.9Hz,1H),6.22(t,J=2.3Hz,1H),6.01(d , J=2.3Hz, 2H), 3.65–3.34 (m, 8H), 2.37 (s, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ168.08 (d, J=21.3Hz), 160.53, 154.14 (D, J = 13.8Hz), 138.87,136.88,132.00,131.88,131.08,129.67,129.65,129.06, 128.72,126.70, 119.94,116.45,15,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5,5. , J＝26.3Hz), 21.55. ¹⁹ F NMR(376MHz, Chloroform-d)δ-161.88(s, 1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝98 /2,1mL/min,254nm,τR(major)=16.66min,τR(minor)=19.44min.

Example 101

Ib-35, white solid; mp: 81-85°C; [α] _D ²⁵ 31.2 (c 0.40, CHCl ₃ ); 96% yield, 98% ee. ¹ HNMR (400 MHz, Chloroform-d) δ 7.85 (dd , J=6.7, 3.0Hz, 2H), 7.57–7.37 (m, 3H), 7.24–7.03 (m, 3H), 6.95–6.74 (m, 2H), 3.84 (ddd, J=11.2, 6.9, 4.2Hz ,1H),3.61–3.31(m,2H), 1.86–1.72(m,1H),1.72–1.52(m,4H),1.31–0.98(m,6H). ¹³ C NMR(101MHz, Chloroform-d) δ168.54(d, J＝20.8Hz), 152.91(d, J＝13.7Hz), 130.54, 130.13, 129.02, 128.25, 127.71, 126.30, 126.29, 96.54, 94.56, 52.84, 40.76(d, J＝26.1Hz ), 30.13, 30.00, 25.22, 25.08. ¹⁹ F NMR(376MHz, Chloroform-d)δ-165.69(s, 1F).HPLC conditions: ChiralcelOJ-H column(250×4.6mm),hexane/i-PrOH＝99 /1,0.5mL/min,254nm,τR(major)=15.05min,τR(minor)=12.07min. .

Example 102

Preparation of (R)-pyrazolone chiral fluorination product Ib-27 (catalyst recycling)

Weigh 1 mmol of 4-substituted pyrazolone Ia-27, add 0.5 mol% phase transfer catalyst IIa-12, put it into a 100 mL reaction flask, add 5 mL of 38wt% K ₂ HPO ₄ aqueous solution, 50 mL of toluene, add 1.05 mL of toluene under stirring at 20°C mmol NFSI (first charge). After reaction 30min, HPLC measures the conversion ratio and ee value of reaction, further adds 1mmol 4-substituted pyrazolone Ia-27 in the system, 1.05mmol NFSI (feeding for the second time) continues stirring reaction 30min, HPLC measures the conversion of reaction Continue feeding after the rate and ee value. The reaction was fed ten times in total, and the reaction time, conversion rate and ee value of each feed were shown in Table 10.

The reaction time, conversion rate and ee value of each feeding of table 10

After the tenth feeding for 30 min, 30 mL of ethyl acetate was added, and the organic layers were combined. The organic layer was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate and concentrated (>99% yield, 95.5% ee). The crude product was directly crystallized with anhydrous ethanol to obtain 3.75 g of product, the total yield was 81%, and the measured ee value was 99.7%.

The basic principles, main features and advantages of the present invention have been shown and described above. Without departing from the spirit and scope of the present invention, the present invention has various changes and improvements, which all fall into the claimed invention. range.

Claims (10)

1. a high-efficiency phase-transfer catalyzed 4-substituted pyrazolone compound asymmetric fluorination method is characterized in that concrete process is: by 4-substituted pyrazolone compound Ia, phase-transfer catalyst and electrophilic fluorination reagent in The solvent is stirred and mixed evenly, then an alkali is added, and the chiral α-fluoropyrazolone compound Ib is obtained by stirring at -78 to 60° C. The reaction equation in the preparation process is:

Wherein R ₁ is phenyl or substituted phenyl, and the substituent on the substituted phenyl benzene ring is F, Cl, Br, I, methoxy, C _1-4 alkyl, nitro, acetonitrile or trifluoromethane base, R ₂ is methyl, ethyl or substituted ethyl, the substituent on the substituted ethyl is phenyl, substituted phenyl, naphthyl or alkynyl, and the substituent on the substituted phenyl benzene ring is F, Cl , Br, I, methoxy, C _1-4 alkyl, nitro, acetonitrile or trifluoromethyl, R ₃ is C _1-4 alkyl, phenyl, substituted phenyl or naphthyl, the substituted benzene The substituents on the phenyl ring are F, Cl, Br, I, methoxy, C _1-4 alkyl, nitro, acetonitrile, methylenedioxy or trifluoromethyl; Described phase transfer catalyst is cinchona base cinchonine derivative IIa or IIb, and its corresponding structural formula is:

wherein R ₃ is H or methoxy, R ₄ is tert-butyl, adamantyl, isopropyl, benzyl or substituted aryl; The structural formula of the electrophilic fluorinating reagent is:

wherein R ₆ is H, methoxy, methyl, chlorine, bromine or iodine. 2. the 4-substituted pyrazolone compound asymmetric fluorination method of efficient phase transfer catalysis according to claim 1, is characterized in that the concrete synthesis process of described phase transfer catalyst cinchona base cinchonine derivative IIa or IIb is : use primary amine to react with bromoacetyl bromide to generate bromoamide, then further react with cinchona alkaloid in tetrahydrofuran to obtain phase transfer catalyst cinchona alkaloid cinchonine derivative IIa or IIb; the corresponding synthetic route is:

3 . The high-efficiency phase transfer catalyzed asymmetric fluorination method for 4-substituted pyrazolones according to claim 1 , wherein the solvent is halogenated hydrocarbon, aromatic hydrocarbon, alkane or ether. 4 . 4. the 4-substituted pyrazolone compound asymmetric fluorination method of efficient phase transfer catalysis according to claim 1 and 3, is characterized in that: described solvent is toluene, trifluorotoluene, chloroform, p-xylene, One or more of mesitylene or n-hexane. 5. the 4-substituted pyrazolone compound asymmetric fluorination method of efficient phase transfer catalysis according to claim 1, is characterized in that: described alkali is organic alkali or inorganic alkali aqueous solution; This inorganic alkali aqueous solution is sodium carbonate , one or more aqueous solutions of dipotassium hydrogen phosphate, potassium phosphate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride or potassium acetate. 6 . The high-efficiency phase-transfer catalyzed asymmetric fluorination method for 4-substituted pyrazolone compounds according to claim 1 , wherein the reaction temperature is -20 to 25° C. 7 . 7. the 4-substituted pyrazolone compound asymmetric fluorination method of efficient phase transfer catalysis according to claim 1, is characterized in that: described phase transfer catalyst consumption is the 4-substituted pyrazolone compound Ia consumption 0.01-10 mol%. 8. the 4-substituted pyrazolone compound asymmetric fluorination method of efficient phase transfer catalysis according to claim 1, is characterized in that: described phase transfer catalyst consumption is the amount of 4-substituted pyrazolone compound Ia consumption 0.5-1 mol%. 9. the 4-substituted pyrazolone compound asymmetric fluorination method of efficient phase transfer catalysis according to claim 1, is characterized in that: described electrophilic fluorination reagent and 4-substituted pyrazolone compound Ia The feeding molar ratio is 1-2:1. 10 . The high-efficiency phase-transfer catalyzed asymmetric fluorination method for 4-substituted pyrazolone compounds according to claim 1 , wherein the reaction time is 10 min to 1 h. 11 .