CN113501766B - Asymmetric synthesis method of multi-functional cyclopentenone derivative containing difluoroalkyl - Google Patents

Asymmetric synthesis method of multi-functional cyclopentenone derivative containing difluoroalkyl Download PDF

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CN113501766B
CN113501766B CN202110770331.3A CN202110770331A CN113501766B CN 113501766 B CN113501766 B CN 113501766B CN 202110770331 A CN202110770331 A CN 202110770331A CN 113501766 B CN113501766 B CN 113501766B
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蔡云飞
钟思师
杨倩
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Chongqing University
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Abstract

The invention provides an asymmetric synthesis method of a multi-functional cyclopentenone derivative containing a difluoro alkyl group. The chiral multifunctional cyclopentenone derivative containing difluoro alkyl is synthesized by combining visible light catalysis, chiral Bronsted acid and achiral Lewis acid catalysis, and carrying out asymmetric three-component aza-Piancateli rearrangement reaction by taking furan alkene, difluoro alkyl halide and aromatic amine compound as raw materials. The method has mild reaction conditions, high yield, excellent enantioselectivity and diastereoselectivity and potential application value in the aspect of drug synthesis.

Description

Asymmetric synthesis method of multi-functional cyclopentenone derivative containing difluoroalkyl
Technical Field
The invention belongs to the field of asymmetric synthesis in organic chemistry, and particularly relates to an asymmetric synthesis method of a multi-functional cyclopentenone derivative containing difluoro alkyl groups.
Background
Because of the unique properties of fluorine atoms, fluorine-containing organic compounds are widely used in the fields of medicine, pesticides, functional materials, life sciences, and the like. The introduction of difluoroalkyl can obviously improve the metabolic stability and the oral bioavailability of molecules, and has become an important means for drug development. However, there is no report on a method of introducing a difluoroalkyl group in a cyclopentenone side chain which is an important intermediate for organic synthesis. Therefore, it is of great importance to develop a simple and efficient method for achieving asymmetric synthesis of a multi-functional cyclopentenone derivative containing a difluoroalkyl group.
Disclosure of Invention
The invention aims to provide an asymmetric synthesis method of a multi-functional cyclopentenone derivative containing a difluoroalkyl group.
In order to achieve the above purpose, the technical scheme adopted by the invention comprises the following steps:
step S1, carrying out free radical mediated three-component difluoroalkylation amination reaction by taking furan alkene, aromatic amine compound and difluoroalkyl halide as raw materials under visible light, wherein the reaction formula is as follows:
Figure GDA0004174641170000011
step S2 is to take intermediate IV, add chiral bronsted acid (b×h) and achiral Lewis Acid (LA), and perform an asymmetric rearrangement reaction in an organic solvent to obtain product V, which has the following reaction formula:
Figure GDA0004174641170000012
wherein the method comprises the steps of
R is phenyl, 2-naphthyl or benzene ring containing substituent, and the substituent on the benzene ring is one of methyl, methoxy or halogen;
R 1 is H or methyl;
ar is benzene ring connected with different groups of electron withdrawing or electron donating, wherein the different groups are one or two of methyl, methoxy, halogen, ester, trifluoromethyl, benzoyl or acetyl.
R F The raw material of the difluoroalkyl halide is selected from one of the following structural formulas of the compounds:
Figure GDA0004174641170000021
the photocatalyst described in step S1 is mer-Ir (ppy) 3 The alkali is potassium carbonate, and the reaction temperature is room temperature;
the achiral Lewis acid in the step S2 is dysprosium triflate, and the reaction temperature is room temperature;
the chiral bronsted acid in step S2 has the following structural formula:
Figure GDA0004174641170000022
the implementation operation of the technical scheme comprises the following steps:
step S1, photo-catalyst mer-Ir (ppy) 3 And K 2 CO 3 Placing the mixture in a reaction tube, and placing a magnetic stirrer with proper size. And (3) vacuumizing and drying, replacing three times by using argon, and adding acetonitrile under the protection of the argon. Then furan alkene, aromatic amine compound and difluoro alkyl halide are added in turn. The reaction mixture was degassed with argon for 5 min, then reacted at room temperature under blue LED lamp irradiation, and the reaction was monitored by TLC. When TLC showed complete conversion of arylamine compounds (t 1 ) The reaction mixture was filtered through celite, washed with dichloromethane and concentrated to give crude intermediate IV which was used directly in the next step.
Step S2 Dy (OTf) 3 And Bronsted acid A1 are placed in a reaction tube and placed in a magnetic stirrer of suitable size. Vacuum drying, replacing three times with argon, adding chloroform under the protection of argon, and stirring for 1 min at room temperature. Subsequently, intermediate IV obtained in step 1 was dissolved in chloroform and added to the reaction mixture to react at room temperature. After the reaction is finishedAdult (t) 2 ) After flash column chromatography, 1,3, 5-trimethoxybenzene was used as an internal standard to perform 1 H NMR characterization to determine the nuclear magnetic yield and dr values of the product. The crude product was further purified by column chromatography on silica gel to give the major diastereoisomer of the product and its corresponding isolated yields. The ee value is determined by chiral analysis by liquid chromatography (HPLC).
In the preparation method, the dosage ratio of furan alkene, aromatic amine compound and difluoroalkyl halide in the reaction in the step S1 is 0.24 mmol/0.20 mmol/0.40 mmol.
In the preparation method of the invention, the mer-Ir (ppy) in the step S1 reaction 3 The molar amount of (C) is 0.33% of that of the arylamine compound.
In the preparation method, the dosage ratio of the potassium carbonate to the arylamine compound in the reaction in the step S1 is 0.4mmol to 0.20mmol.
In the preparation method of the invention, the reaction time t in the step S1 reaction 1 10-96h.
In the preparation method, the organic solvent in the reaction in the step S1 is acetonitrile, the volume ratio of the substance amount of the arylamine compound to the acetonitrile is 0.1 mmol/2 mL, and the reaction is carried out in an argon atmosphere.
In the preparation method, visible light is provided by a blue LED lamp with the power of 3W and the wavelength of 460-465nm in the reaction in the step S1, and the distance between the blue lamp and the reactant is 4cm.
In the preparation method of the invention, dy (OTf) in the reaction of the step S2 3 The molar dosage of the chiral Bronsted acid A1 is 0.33 percent and 1 percent of that of the arylamine compound respectively.
In the preparation method of the invention, the organic solvent in the step S2 reaction is chloroform, the solvent dosage is 2mL, and the reaction time t is 2 3-120h.
The asymmetric synthesis method of the multi-functional cyclopentenone derivative containing the difluoro alkyl group has the advantages of mild reaction conditions, excellent enantioselectivity and diastereoselectivity, high chemical yield and potential practical application value in the aspect of drug synthesis.
The specific embodiment is as follows:
the monitoring method in any one of the embodiments of the present invention is: thin layer chromatography.
The structural validation techniques are all general techniques known to those skilled in the art: nuclear magnetic resonance technology, high resolution mass spectrometry.
The invention will be further illustrated with reference to the following examples, which are not intended to limit the same.
Example 1
Synthetic route for 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-1) of the present invention:
Figure GDA0004174641170000041
step 1, photo-catalyst mer-Ir (ppy) 3 (1.3 mg,0.002 mmol) and K 2 CO 3 (55.3 mg,0.4mmol,2.0 eq) was placed in a reaction tube and a magnetic stirrer of suitable size was placed. Vacuum drying, replacing three times with argon, and adding 2mL of acetonitrile under the protection of argon. Then 2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), o-chloroaniline (0.20 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.40 mmol,2.0 eq) were added sequentially. The reaction mixture was degassed with argon for 5 minutes and then reacted at room temperature under irradiation of a blue LED lamp with a power of 3W, and the reaction was monitored by TLC. When TLC showed complete conversion of arylamine compounds (t 1 =10 h), the reaction mixture was filtered through celite, washed with dichloromethane and concentrated to give crude intermediate IV which was used directly in the next step.
Step 2 Dy (OTf) 3 (0.4 mg,0.0066 mol) and Bronsted acid A1 (1.8 mg, 0.002mmol). Placing the mixture in a reaction tube, and placing a magnetic stirrer with proper size. Vacuum drying, three times with argon substitution, adding chloroform (0.5 mL) under argon protection and stirring at room temperature for 1 min. Subsequently, intermediate IV obtained in step 1 was dissolved in chloroform (1.5 mL) and added to the reaction mixture to react at room temperature. After completion of the reaction (t 2 =48 h), viaAfter flash column chromatography, 1,3, 5-trimethoxybenzene was used as an internal standard for 1 H NMR characterization to determine the nuclear magnetic yield and dr values of the product. The crude product was further purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1-8/1) to give ethyl 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate. The nuclear magnetic yield is 77% and the isolation yield is 72%. The ee value is determined analytically by HPLC.
Characterization data of the resulting structural formula 1:
yellow oil, 77% nuclear magnetic yield, 72% isolation yield, 18/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝14.1min,t r (minor)＝11.0min；[α] D 20 ＝–98.7(c＝0.82,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.56(m,1H),7.30–7.26(m,3H),7.21–7.13(m,2H),7.08–7.02(m,2H),6.90(d,J＝8.2Hz,1H),6.65(t,J＝7.6Hz,1H),6.59(d,J＝5.7Hz,1H),5.44(d,J＝10.3Hz,1H),4.31(q,J＝7.1Hz,2H),3.84(d,J＝10.4Hz,1H),3.28–3.00(m,2H),1.34(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.5(t,J＝32.8),161.7,142.0,138.3,134.6,129.5,128.8,128.1,128.0,127.7,119.9,118.3,115.5(t,J＝251.8Hz),111.5,63.4,59.8(t,J＝6.3Hz),57.4,39.0(t,J＝21.7Hz),13.9. 19 F NMR(377MHz,CDCl 3 )δ-95.8(d,J＝262.2Hz),-102.2(d,J＝262.3Hz).HRMS(ESI)m/z calcd.For C 22 H 20 ClF 2 NNaO 3 [M+Na] + 442.0992,found 442.1010.
Example 2
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (4-methoxyphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-2):
Figure GDA0004174641170000051
with 2- (1- (4-methoxyphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 e)q) is used as a reaction raw material, and the reaction time is t 1 ＝16h,t 2 =16h, the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) to obtain yellow oily product V-2 with nuclear magnetic resonance yield of 60% and isolation yield of 57%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝15.3min,t r (minor)＝12.6min；[α] D 20 ＝–101.6(c＝0.88,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.56(m,1H),7.22–7.13(m,2H),6.98(d,J＝7.3Hz,2H),6.90(d,J＝8.1Hz,1H),6.80(d,J＝7.3Hz,2H),6.66(t,J＝7.6Hz,1H),6.59–6.56(m,1H),5.39(d,J＝10.2Hz,1H),4.30(q,J＝7.3,5.0Hz,2H),3.87(d,J＝11.4Hz,1H),3.77(s,3H),3.20–2.95(m,2H),1.34(t,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.7(t,J＝32.1),161.6,159.1,142.1,134.4,130.2,129.5,128.9,128.0,119.9,118.2,115.2(t,J＝260.4Hz),114.2,111.6,63.4,59.7–59.2(m),56.8,55.4,39.1(t,J＝22.4Hz),13.9. 19 F NMR(377MHz,CDCl 3 )δ-95.9(d,J＝262.2Hz),-102.5(d,J＝262.3Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 4 [M+Na] + 472.1098,found 472.1104.
Example 3
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (4-methylphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-3):
Figure GDA0004174641170000061
2- (1- (4-methylphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝16h,t 2 =16h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=8/1-6/1) gives the product V-3 as a yellow oil, nucleiThe magnetic yield is 54%, the separation yield is 52%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝11.0min,t r (minor)＝8.9min；[α] D 20 ＝–92.9(c＝0.90,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.59–7.56(m,1H),7.20–7.13(m,2H),6.97(d,J＝8.7Hz,2H),6.90(d,J＝8.2Hz,1H),6.80(d,J＝8.6Hz,2H),6.65(t,J＝7.6Hz,1H),6.58–6.54(m,1H),5.39(d,J＝10.3Hz,1H),4.29(q,J＝7.1Hz,2H),3.87(d,J＝10.3Hz,1H),3.76(s,3H),3.25–2.94(m,2H),1.34(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.5(t,J＝29.2Hz),161.7,159.1,142.0,134.4,130.2,129.5,128.9,128.0,119.9,118.2,115.4(t,J＝223.9Hz),114.2,111.5,63.4,59.9–59.7(m),56.8,55.4,39.1(t,J＝22.0Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝262.5Hz),-102.4(d,J＝262.1Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 3 [M+Na] + 456.1148,found 456.1154.
Example 4
3- ((1 r,2 r) -1- ((1, 1' -biphenyl) -4-yl) -2- ((chlorophenyl) amino) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-4):
Figure GDA0004174641170000062
2- (1- ((1, 1' -biphenyl) -4-yl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝10h,t 2 =34 h, the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) to obtain yellow solid product V-4 with nuclear magnetic resonance yield of 54% and separation yield of 51%,>20/1dr. HPLC analysis gave 93% ee (Chiralcel AD-H, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝13.9min,t r (minor)＝18.4min；[α] D 20 ＝–26.9(c＝0.90,in CHCl 3 )；mp＝123–125℃. 1 H NMR(500MHz,CDCl 3 )δ7.65–7.60(m,1H),7.52(d,J＝7.4Hz,2H),7.48(d,J＝8.2Hz,2H),7.43(t,J＝7.5Hz,2H),7.35(t,J＝7.2Hz,1H),7.19(t,J＝7.8Hz,1H),7.14(d,J＝7.9Hz,1H),7.10(d,J＝8.2Hz,2H),6.93(d,J＝8.2Hz,1H),6.66(t,J＝7.6Hz,1H),6.61(d,J＝5.7Hz,1H),5.48(d,J＝10.0Hz,1H),4.32(q,J＝7.1Hz,2H),3.90(d,J＝10.5Hz,1H),3.30–3.01(m,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.6(t,J＝31.6Hz),161.9,142.0,140.9,140.3,137.2,134.6,129.6,128.7,128.0,127.6,127.4,127.1,120.0,118.4,115.6(t,J＝253.2Hz),111.6,63.5,60.0(t,J＝3.6Hz),57.3,39.0(t,J＝21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝262.6Hz),-102.3(d,J＝262.7Hz).HRMS(ESI)m/z calcd.For C 28 H 24 ClF 2 NNaO 3 [M+Na] + 518.1305,found 518.1312.
Example 5
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (4-fluorophenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-5):
Figure GDA0004174641170000071
2- (1- (4-fluorophenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝10h,t 2 =11h, the rest of the procedure is the same as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1-5/1) afforded the product V-5 as a yellow oil in 80% nuclear magnetic yield, 74% isolation yield, 19/1dr. HPLC analysis gave 96% ee (FLM Chiral NS, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝8.3min,t r (minor)＝10.3min；[α] D 20 ＝–105.1(c＝0.92,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.21–7.14(m,2H),7.04–6.99(m,2H),6.95(t,J＝8.5Hz,2H),6.91(d,J＝8.1Hz,1H),6.67(t,J＝7.6Hz,1H),6.60–6.56(m,1H),5.48–5.35(m,1H),4.31(q,J＝7.1Hz,2H),3.79(br,1H),3.20–2.99(m,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.2,163.4(t,J＝32.4Hz),162.1(d,J＝248.7Hz),161.8,141.8,134.1(d,J＝3.1Hz),134.1,129.6(d,J＝2.4Hz),129.5,128.1,119.9,118.5,115.6(d,J＝21.5Hz),115.5(t,J＝253.7Hz),111.6,63.5,60.0(t,J＝3.0Hz),56.9,39.4(t,J＝22.2Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-96.1(ddd,J＝263.0,24.7,14.0Hz),-102.2(ddd,J＝263.0,19.9,12.7Hz),-113.9–-113.9(m).HRMS(ESI)m/z calcd.For C 22 H 19 ClF 3 NNaO 3 [M+Na] + 460.0898,found 460.0903.
Example 6
3- ((1 r,2 r) -1- (4-chlorophenyl) -2- ((2-chlorophenyl) amino) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-6):
Figure GDA0004174641170000081
2- (1- (4-chlorophenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝16h,t 2 =16h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1-8/1) gave the product V-6 as a yellow oil in a nuclear magnetic yield of 39%, isolation yield of 34%,13/1dr. HPLC analysis gave 91% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝15.7min,t r (minor)＝12.6min；[α] D 20 ＝–77.3(c＝0.64,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.60(m,1H),7.23(d,J＝8.0Hz,2H),7.18(t,J＝8.4Hz,2H),6.97(d,J＝7.9Hz,2H),6.91(d,J＝8.0Hz,1H),6.68(t,J＝7.5Hz,1H),6.58(d,J＝5.2Hz,1H),5.45(d,J＝10.7Hz,1H),4.31(q,J＝6.9Hz,2H),3.80(d,J＝10.6Hz,1H),3.22–2.96(m,2H),1.35(t,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ206.9,163.3(t,J＝32.3Hz),161.8,141.8,136.8,134.5,134.1,130.4,129.6,129.1,128.8,128.3,128.1,127.8,120.0,118.6,116.0(t,J＝252.8Hz),111.6,60.0(t,J＝3.8Hz),57.1,39.2(t,J＝22.1Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-96.0(d,J＝262.9Hz),-102.2(d,J＝263.3Hz).HRMS(ESI)m/z calcd.For C 22 H 19 Cl 2 F 2 NNaO 3 [M+Na] + 476.0602,found 476.0608.
Example 7
3- ((1 r,2 r) -1- (4-bromophenyl) -2- ((2-chlorophenyl) amino) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-7):
Figure GDA0004174641170000091
2- (1- (4-bromophenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 ＝10h,t 2 =11h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) gave the product V-7 as a yellow oil, yield 74% nuclear magnetic resonance, isolation yield 63%,9/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝15.6min,t r (minor)＝13.0min；[α] D 20 ＝–93.8(c＝0.88,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.33–7.28(m,3H),7.21(t,J＝7.6Hz,1H),7.10–7.03(m,2H),6.87(d,J＝8.0Hz,1H),6.62–6.56(m,2H),5.42(d,J＝10.2Hz,1H),4.31(q,J＝6.6Hz,2H),3.86(d,J＝10.1Hz,1H),3.31–2.97(m,2H),1.35(t,J＝6.9Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.5(t,J＝32.5Hz),161.6,142.9,138.3,134.6,132.9,128.9,128.7,128.1,127.7,118.8,115.6(t,J＝253.6Hz),111.5,110.4,63.4,59.9(t,J＝3.4Hz),57.3,38.9(t,J＝21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-96.0(d,J＝262.8Hz),-102.1(d,J＝263.0Hz).HRMS(ESI)m/z calcd.For C 22 H 19 BrClF 2 NNaO 3 [M+Na] + 520.0097,found 520.0104.
Example 8
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (2-methoxyphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-8):
Figure GDA0004174641170000092
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2- (1- (2-methoxyphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝16h,t 2 =16h, the reaction solvent used in step 2 was 4mL of chloroform; the catalyst dosage is 2mol percent Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=15/1-10/1) to obtain yellow oily product V-8 with nuclear magnetic resonance yield of 74% and separation yield of 69%,>16/1dr. HPLC analysis gave 92% ee (Chiralcel IA, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝11.6min,t r (minor)＝9.7min；[α] D 20 ＝–53.8(c＝0.78,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.52–7.44(m,1H),7.15(t,J＝6.4Hz,1H),7.08–6.97(m,3H),6.82–6.67(m,3H),6.50(t,J＝6.5Hz,1H),6.45–6.40(m,1H),5.29(s,1H),4.62–4.18(m,3H),3.58(s,3H),3.30(s,1H),3.05(q,J＝16.7Hz,1H),1.35(t,J＝6.7Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ208.8,163.6(t,J＝32.2Hz),156.7,143.4,142.7,133.8,129.7,129.2,129.2,128.4,127.5,120.8,118.9,117.5,114.8(t,J＝253.6Hz),112.1,111.1,63.3,61.4–61.1(m),55.6,54.7,40.0–39.3(m),13.9. 19 F NMR(564MHz,CDCl 3 )δ-99.1(d,J＝264.4Hz),-100.2(d,J＝264.2Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 4 [M+Na] + 472.1098,found 472.1103.
Example 9
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (3-methoxyphenyl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-9):
Figure GDA0004174641170000101
2- (1- (3-methoxyphenyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝16h,t 2 =40 h, the reaction solvent used in step 2 was 4mL chloroform, the catalyst dose was 2mol% dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/chloroform=6/1-4/1) gave the product V-9 as a yellow oil with a nuclear magnetic resonance yield of 49%, a separation yield of 40%,7.2/1dr. HPLC analysis gave 93% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝16.3min,t r (minor)＝13.1min；[α] D 20 ＝–110.6(c＝0.91,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.58(m,1H),7.23–7.13(m,3H),6.91(d,J＝8.1Hz,1H),6.81(d,J＝8.3Hz,1H),6.68–6.57(m,3H),6.54(s,1H),5.43(d,J＝10.5Hz,1H),4.31(q,J＝7.1Hz,2H),3.92(d,J＝10.5Hz,1H),3.65(s,3H),3.24–2.99(m,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.1,162.7(t,J＝34.9Hz),161.7,159.7,142.1,139.6,134.5,129.8,129.5,128.0,119.8,119.8,118.2,115.7(t,J＝249.2Hz),113.9,113.4,111.5,63.4,59.8(t,J＝2.7Hz),57.4,55.2,39.0(t,J＝21.8Hz),13.9. 19 F NMR(377MHz,CDCl 3 )δ-95.6(d,J＝262.2Hz),-102.5(d,J＝262.3Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 4 [M+Na] + 472.1098,found 472.1102.
Example 10
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1- (m-methylphenyl) cyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-10):
Figure GDA0004174641170000111
2- (1- (m-tolyl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 ＝20h,t 2 =3h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=8/1-6/1) to obtain yellow oily product V-10 with nuclear magnetic resonance yield of 42% and separation yield of 39%,>20/1dr. HPLC analysis gave 89% ee (FLM Chiral NS, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝6.1min,t r (minor)＝8.0min；[α] D 20 ＝–78.5(c＝0.45,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.60–7.57(m,1H),7.22–7.13(m,3H),7.08(d,J＝7.5Hz,1H),6.91(d,J＝8.2Hz,1H),6.82(d,J＝10.0Hz,2H),6.65(t,J＝7.6Hz,1H),6.58(d,J＝5.7Hz,1H),5.43(s,1H),4.30(q,J＝7.1Hz,2H),3.87(br,1H),3.25–2.96(m,2H),2.23(s,3H),1.34(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.5,163.6(t,J＝62.5Hz),161.7,142.1,138.5,138.1,134.5,129.5,128.8,128.7,128.5,128.0,124.6,119.8,118.2,115.6(t,J＝253.6Hz),111.5,63.4,59.8(t,J＝3.5Hz),57.4,39.1(t,J＝21.9Hz),21.6,13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.7(d,J＝261.8Hz),-102.4(d,J＝262.5Hz).HRMS(ESI)m/z calcd.For C 23 H 22 ClF 2 NNaO 3 [M+Na] + 456.1148,found 456.1153.
Example 11
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -1- (naphthalen-2-yl) -5-oxocyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-11):
Figure GDA0004174641170000121
2- (1- (naphthalene-2-yl) vinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝16h,t 2 =3h, use in step 2The reaction temperature of (2) is 10 ℃, the reaction solvent is 4mL of chloroform, and the catalyst dosage is 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/chloroform=10/1-8/1) to obtain yellow oily product V-11 with nuclear magnetic resonance yield of 52% and separation yield of 50%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝13.8min,t r (minor)＝13.0min；[α] D 20 ＝–49.6(c＝0.81,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.78(d,J＝7.6Hz,1H),7.74(d,J＝8.7Hz,1H),7.69(d,J＝7.6Hz,1H),7.64–7.60(m,1H),7.50–7.43(m,3H),7.22–7.15(m,2H),7.07(d,J＝7.9Hz,1H),6.96(d,J＝8.2Hz,1H),6.70–6.61(m,2H),5.52(d,J＝10.0Hz,1H),4.32(q,J＝7.2Hz,2H),3.87(d,J＝10.6Hz,1H),3.39–3.12(m,2H),1.35(t,J＝7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.2,163.6(t,J＝34.4Hz),161.8,142.0,135.5,134.5,133.0,132.5,129.5,128.4,128.2,128.0,127.4,127.4,126.7,126.5,125.2,119.9,118.3,115.7(t,J＝253.3Hz),111.6,63.5,60.0(t,J＝3.2Hz),57.7,39.3(t,J＝21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.2–-96.3(m),-101.9–-102.8(m).HRMS(ESI)m/z calcd.For C 26 H 22 ClF 2 NNaO 3 [M+Na] + 492.1148,found 492.1173.
Example 12
3- ((1 r,2 r) -2- ((2-bromophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-12):
Figure GDA0004174641170000122
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-bromoaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝16h,t 2 =10h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (Stone)Oil ether/ethyl acetate=8/1-6/1), to give the product V-12 as a yellow oil, a nuclear magnetic yield of 42%, a separation yield of 39%,>20/1dr. HPLC analysis gave 95% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝14.4min,t r (minor)＝10.1min；[α] D 20 ＝–131.6(c＝0.8,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.34–7.27(m,4H),7.21(t,J＝7.5Hz,1H),7.11–7.04(m,2H),6.87(d,J＝8.1Hz,1H),6.63–6.55(m,2H),5.42(d,J＝10.2Hz,1H),4.31(q,J＝6.6Hz,2H),3.86(d,J＝10.1Hz,1H),3.27–3.00(m,2H),1.35(t,J＝6.9Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.5(t,J＝32.4Hz),161.6,142.9,138.3,134.5,132.8,128.9,128.7,128.1,127.7,118.8,115.63(dd,J＝255.8,250.4Hz),111.5,110.4,63.4,59.9(t,J＝6.3Hz),57.3,38.9(t,J＝21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝262.6Hz),-102.3(d,J＝262.5Hz).HRMS(ESI)m/z calcd.For C 22 H 20 BrF 2 NNaO 3 [M+Na] + 486.0487,found 486.0493.
Example 13
3- ((1 r,2 r) -2- ((2-acetylphenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-13):
Figure GDA0004174641170000131
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 1- (2-aminophenyl) ethan-1-one (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝12h,t 2 =42 h, the rest of the procedure is the same as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1-5/1) gave the product V-13 as a yellow oil in 94% nuclear magnetic yield, 76% isolation yield, 4.8/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝17.5min,t r (minor)＝14.2min；[α] D 20 ＝–410.1(c＝0.89,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.38(d,J＝9.3Hz,1H),7.62(d,J＝7.6Hz,2H),7.40(t,J＝7.8Hz,1H),7.21–7.21(m,3H),6.99(t,J＝8.8Hz,3H),6.64(t,J＝7.6Hz,1H),6.60–6.56(m,1H),5.57(d,J＝8.4Hz,1H),4.31(q,J＝7.1Hz,2H),3.26–3.05(m,2H),2.35(s,3H),1.34(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.7,200.3 163.6(t,J＝32.4Hz),161.9,149.3,138.6,135.1,134.6,132.9,128.4,127.7,127.6,118.6,115.7(t,J＝250.4Hz),115.4,111.9,63.4,60.0–59.9(m),57.6,39.3(t,J＝21.9Hz),27.8,13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.9(ddd,J＝262.1,25.2,14.3Hz),-102.4(ddd,J＝262.1,20.1,12.8Hz).HRMS(ESI)m/z calcd.For C 24 H 23 F 2 NNaO 4 [M+Na] + 450.1487,found 450.1508.
Example 14
3- ((1 r,2 r) -2- ((2-benzoylphenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-14):
Figure GDA0004174641170000141
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), (2-aminophenyl) (phenyl) methanone (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝16h,t 2 =10h, 4mL chloroform as reaction solvent used in step 2, 2mol% dy (OTf) as catalyst 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-14 as a yellow oil, 77% nuclear magnetic resonance yield, 73% isolation yield, 8.5/1dr. HPLC analysis gave 90% ee (Chiralcel OD, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝12.6min,t r (minor)＝16.5min；[α] D 20 ＝–358.6(c＝0.89,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.05(d,J＝10.0Hz,1H),7.70–7.65(m,1H),7.50–7.44(m,1H),7.44–7.37(m,5H),7.33(t,J＝7.7Hz,1H),7.15–7.03(m,4H),6.99(d,J＝7.3Hz,2H),6.64–6.52(m,2H),5.65(d,J＝10.0Hz,1H),4.32(q,J＝6.8Hz,2H),3.34–3.09(m,2H),1.35(t,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.8,198.5,163.6(t,J＝32.3Hz),161.8,149.9,139.9,138.6,135.6,135.0,134.9,130.9,129.0,128.4,127.9,127.6,127.6,118.2,115.8(t,J＝253.5Hz),115.1,111.9,63.4,60.0,57.7,39.4(t,J＝21.8Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝261.7Hz),-102.3(d,J＝262.0Hz).HRMS(ESI)m/z calcd.For C 29 H 25 F 2 NNaO 4 [M+Na] + 512.1644,found 512.1652.
Example 15
Methyl 2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenyl-cyclopent-2-en-1-yl) amino) benzoate (V-15):
Figure GDA0004174641170000151
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-aminobenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 ＝53h,t 2 =12h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) gave the product V-15 as a yellow oil in a nuclear magnetic yield of 68%, isolation yield of 50%,3/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝14.4min,t r (minor)＝11.8min；[α] D 20 ＝–259.5(c＝0.99,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.77(d,J＝8.0Hz,1H),7.64–7.60(m,1H),7.40(t,J＝7.8Hz,1H),7.23–7.08(m,4H),7.03–6.94(m,3H),6.64(t,J＝7.6Hz,1H),6.59(d,J＝5.7Hz,1H),5.58(s,1H),4.31(q,J＝7.1Hz,2H),3.61(s,3H),3.31–2.95(m,2H),2.43(br,1H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.9,168.0,163.6,162.1,149.3,138.8,134.7,134.6,131.9,128.35,127.7,127.5,116.0,111.7,115.7(t,J＝253.3Hz),111.4,63.4,60.2–60.0(m),57.8,51.4,39.4(t,J＝21.4Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(ddd,J＝262.1,25.3,14.2Hz),-102.4(ddd,J＝262.1,20.4,13.1Hz).HRMS(ESI)m/z calcd.For C 24 H 23 F 2 NNaO 5 [M+Na] + 466.1437,found 466.1457.
Example 16
3- ((1 r,2 r) -2- ((3-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-16):
Figure GDA0004174641170000152
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 3-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝16h,t 2 =34 h, the reaction solvent used in step 2 was 4mL chloroform, the catalyst dose was 2mol% dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-16 as a yellow solid in 61% nuclear magnetic yield, 51% isolation yield, 5.6/1dr. HPLC analysis gave 72% ee (Chiralcel AD-H, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝10.1min,t r (minor)＝13.7min；[α] D 20 ＝–21.6(c＝0.88,in CHCl 3 )；mp＝89–91℃. 1 H NMR(500MHz,CDCl 3 )δ7.58–7.55(m,1H),7.31–7.27(m,3H),7.09–7.01(m,3H),6.70(d,J＝7.9Hz,1H),6.58–6.52(m,1H),6.42(s,1H),6.37(d,J＝8.2Hz,1H),5.35(d,J＝10.6Hz,1H),4.30(q,J＝7.2Hz,2H),3.25–3.00(m,3H),1.35(t,J＝7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ206.1,162.4(t,J＝32.4Hz),160.8,146.2,137.2,134.1,133.4,129.4,127.6,127.0,126.8,117.4,115.5(t,J＝255.0Hz),112.4,110.5,62.4,59.4(d,J＝4.3Hz),56.4,38.3(t,J＝22.2Hz),12.8. 19 F NMR(564MHz,CDCl 3 )δ-96.0(d,J＝263.4Hz),-102.1(d,J＝263.0Hz).HRMS(ESI)m/z calcd.For C 22 H 20 ClF 2 NNaO 3 [M+Na] + 442.0992,found 442.0997.
Example 17
3- ((1 r,2 r) -2- ((4-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-17):
Figure GDA0004174641170000161
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 4-chloroaniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝20h,t 2 =120 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction temperature used in the step 2 was 15 ℃, the reaction solvent was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1-6/1) gave the product V-17 as a yellow oil in 77% nuclear magnetic yield, 63% isolation yield, 2.7/1dr. HPLC analysis gave 67% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝15.9min,t r (minor)＝17.2min；[α] D 20 ＝–26.7(c＝0.3,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.61–7.54(m,1H),7.31–7.25(m,3H),7.08(d,J＝8.8Hz,2H),7.25–6.99(m,2H),6.59–6.52(m,1H),6.39(d,J＝11.3Hz,2H),5.36(d,J＝10.0Hz,1H),4.30(q,J＝7.2Hz,2H),3.21–2.98(m,3H),1.35(t,J＝7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,163.4(t,J＝32.3Hz),162.1,144.7,138.4,134.5,129.3,128.7,128.0,127.9,123.2,115.6(dd,J＝255.9,251,5Hz),114.7,63.5,60.8(t,J＝2.2Hz),57.6,39.1(t,J＝22.5Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝262.5Hz),-102.3(d,J＝262.5Hz).HRMS(ESI)m/z calcd.For C 22 H 20 ClF 2 NNaO 3 [M+Na] + 442.0992,found 442.0995.
Example 18
2, 2-difluoro-3- ((1 r,5 r) -2-oxo-1-phenyl-5- ((4- (trifluoromethyl) phenyl) amino) cyclopent-3-en-1-yl) propanoate (V-18):
Figure GDA0004174641170000171
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 4- (trifluoromethyl) aniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 ＝16h,t 2 =82 h. The reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-18 as a yellow oil in a nuclear magnetic yield of 65%, isolation yield of 56%,9/1dr. HPLC analysis gave 80% ee (Chiralcel AD-H, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝10.7min,t r (minor)＝13.2min；[α] D 20 ＝–115.1(c＝0.2,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.59–7.54(m,1H),7.38(d,J＝8.2Hz,2H),7.31–7.27(m,3H),7.07–6.99(m,2H),6.61–6.56(m,1H),6.51(d,J＝8.2Hz,2H),5.46(d,J＝10.5Hz,1H),4.31(q,J＝7.4Hz,2H),3.38(d,J＝10.8Hz,1H),3.29–2.99(m,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.1,163.3(t,J＝32.4Hz),161.6,148.7,138.3,134.7,128.7,128.1,127.9,126.9(q,J＝3.6Hz),122.5(q,J＝270.8Hz),120.2(q,J＝32.3Hz),115.6(t,J＝253.0Hz),112.6,63.5,60.1(t,J＝2.5Hz),57.5,39.2(t,J＝22.4Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-61.3(s),-95.9(ddd,J＝262.4,25.1,13.9Hz),-102.3(ddd,J＝259.6,17.1,9.0Hz).HRMS(ESI)m/z calcd.F For C 23 H 20 F 5 NNaO 3 [M+Na] + 476.1256,found 476.1274.
Example 19
2- (((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino) -4-methoxybenzoate (V-19):
Figure GDA0004174641170000181
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-4-methoxybenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝16h,t 2 =10h. The reaction temperature used in the step 2 was 10 ℃, the reaction solvent was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-19 as a yellow oil in a nuclear magnetic yield of 87%, isolation yield of 67%,4/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝12.9min,t r (minor)＝14.7min；[α] D 20 ＝–186.3(c＝0.96,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.71(d,J＝8.9Hz,1H),7.64–7.55(m,1H),7.39(d,J＝10.3Hz,1H),7.20–7.14(m,3H),7.03–6.88(m,2H),6.65–6.56(m,1H),6.50(s,1H),6.21(d,J＝8.9Hz,1H),5.57(d,J＝10.3Hz,1H),4.31(q,J＝7.0Hz,2H),3.86(s,3H),3.58(s,3H),3.31–3.05(m,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.8,167.7,164.9,163.5(t,J＝32.5Hz),162.0,151.4,138.8,134.6,133.7,128.4,127.7,127.5,115.9(dd,J＝256.8,253.2Hz),104.7,103.6,95.5,63.4,60.1–59.9(m),58.0,55.3,51.1,39.6(t,J＝21.8Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.3(d,J＝260.6Hz),-102.7(d,J＝260.6Hz).HRMS(ESI)m/z calcd.For C 25 H 25 F 2 NNaO 6 [M+Na] + 496.1542,found 496.1548.
Example 20
2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino) -4-methylbenzoate (V-20):
Figure GDA0004174641170000182
with 2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-4-methylbenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) as reaction starting materials for a reaction time t 1 ＝11h,t 2 =40 h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=5/1-4/1) gave the product V-20 as a yellow oil in a nuclear magnetic yield of 70%, isolation yield of 53%,3.5/1dr. HPLC analysis gave 93% ee (FLM Chiral NS, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝8.4min,t r (minor)＝9.7min；[α] D 20 ＝–241.9(c＝0.81,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.66(d,J＝8.1Hz,1H),7.63–7.57(m,1H),7.22–7.16(m,4H),7.01–6.94(m,2H),6.83(s,1H),6.60–6.56(m,1H),6.46(d,J＝8.1Hz,1H),5.58(s,1H),4.31(q,J＝7.1Hz,2H),3.58(s,3H),3.26–3.03(m,2H),2.35(s,3H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.9,168.0,163.6,162.2,149.3,145.5,138.8,134.4,131.8,128.4,127.7,127.5,117.3,115.7(t,J＝251.1Hz),112.1,109.0,63.4,60.1–59.9(m),57.9,51.3,39.4(t,J＝21.9Hz),22.2,13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.7(ddd,J＝262.0,25.1,14.4Hz),-102.6(ddd,J＝262.7,20.1,12.9Hz).HRMS(ESI)m/z calcd.For C 25 H 25 F 2 NNaO 5 [M+Na] + 480.1593,found480.1615.
Example 21
2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino-5-fluorobenzoic acid methyl ester (V-21):
Figure GDA0004174641170000191
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-5-fluorobenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝87h,t 2 =40 h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) gave the product V-21 as a yellow oil in a nuclear magnetic yield of 79%, isolation yield 70%,8.6/1dr. HPLC analysis gave 91% ee (Chiralcel OD, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝9.0min,t r (minor)＝9.9min；[α] D 20 ＝–294.0(c＝0.8,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.64–7.56(m,1H),7.49–7.43(m,1H),7.20–7.13(m,4H),7.06(d,J＝10.3Hz,1H),6.94(t,J＝11.6Hz,3H),6.62–6.58(m,1H),5.53(d,J＝10.4Hz,1H),4.31(q,J＝7.0Hz,2H),3.62(s,3H),3.28–2.93(m,2H),1.35(t,J＝7.1Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.7,167.0(d,J＝2.6Hz),163.5(t,J＝32.4Hz),161.8,153.6(d,J＝235.4Hz),146.1,138.7,134.7,128.3,127.7,127.5,122.2(d,J＝22.9Hz),117.3(d,J＝23.4Hz),115.7(dd,J＝255.7,250.2Hz),113.0(d,J＝7.6Hz),111.6(d,J＝6.4Hz),60.8–60.5(m),57.7,51.7,39.4(t,J＝21.8Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝261.7Hz),-102.4(d,J＝262.0Hz),-128.4(s).HRMS(ESI)m/z calcd.For C 24 H 22 F 3 NNaO 5 [M+Na] + 484.1342,found 484.1348.
Example 22
Methyl 5-chloro-2- ((1 r,5 r) -5- (3-ethoxy-2, 2-difluoro-3-oxopropyl) -4-oxo-5-phenylcyclopent-2-en-1-yl) amino) benzoate (V-22):
Figure GDA0004174641170000201
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-amino-5-chlorobenzoate (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝48h,t 2 =18h, the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) gave the product V-22 as a yellow solid in a nuclear magnetic yield of 76%, isolation yield of 70%,14/1dr. HPLC analysis gave 90% ee (FLM Chiral INB, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝13.6min,t r (minor)＝12.4min；[α] D 20 ＝–214.9(c＝0.87,in CHCl 3 )；mp＝64–66℃. 1 H NMR(500MHz,CDCl 3 )δ7.74(s,1H),7.65–7.52(m,1H),7.34(d,J＝8.9Hz,1H),7.24–7.13(m,4H),6.95(s,3H),6.64–6.57(m,1H),5.53(d,J＝10.2Hz,1H),4.31(q,J＝6.9Hz,2H),3.62(s,3H),3.26–3.01(m,2H),1.35(t,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.5,167.0,163.5(t,J＝32.5Hz),161.5,147.9,138.6,134.8,134.5,131.2,128.4,127.7,127.6,120.6,115.7(t,J＝256.4,253.4Hz),113.2,112.3,63.5,60.3–60.2(m),57.7,51.7,39.4(t,J＝21.9Hz),13.9. 19 F NMR(564MHz,CDCl 3 )δ-95.8(d,J＝261.9Hz),-102.4(d,J＝262.0Hz).HRMS(ESI)m/z calcd.For C 24 H 22 ClF 2 NNaO 5 [M+Na] + 500.1047,found500.1053.
Example 23
3- ((1 r,2 r) -2- ((4-chlorophenyl) (methyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-23):
Figure GDA0004174641170000211
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), N-methyl-4- (trifluoromethyl) aniline (0.2 mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝87h,t 2 =40 h, the reaction solvent used in step 2 was 4mL chloroform, the catalyst dose was 2mol% dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow solid product V-23 with nuclear magnetic resonance yield of 77%, separation yield of 75%,>20/1dr. HPLC analysis gave 60% ee (FLM Chiral INB, hexane/i-PrOH=95/5, flow rate=1.0 mL/min, l=254 nm), t r (major)＝15.9min,t r (minor)＝15.0min；[α] D 20 ＝60.2(c＝0.99,in CHCl 3 )；mp＝107–109℃. 1 H NMR(500MHz,CDCl 3 )δ7.53(d,J＝7.8Hz,3H),7.24–7.14(m,3H),6.96(d,J＝7.6Hz,2H),6.82(d,J＝8.2Hz,2H),6.64–6.60(m,1H),5.89(s,1H),4.32(q,J＝7.0Hz,2H),3.22–2.99(m,2H),1.84(s,3H),1.35(t,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.3(t,J＝32.4Hz),161.2,151.0,138.3,134.8,128.5,128.2,127.7,127.0(q,J＝271.1Hz),125.0(q,J＝3.5Hz),118.7(q,J＝32.8Hz),115.6(t,J＝256.5,251.2Hz),111.0,66.0,60.4,58.1,41.9(t,J＝21.7Hz),33.5,13.9. 19 F NMR(564MHz,CDCl 3 )δ-61.0(s),-95.6(ddd,J＝261.9,25.6,15.0Hz),-102.1(ddd,J＝262.0,19.7,12.9Hz).HRMS(ESI)m/z calcd.For C 24 H 22 F 5 NNaO 3 [M+Na] + 490.1412,found 490.1417.
Example 24
(4 r,5 r) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3-oxo-3-phenylpropyl) -5-phenylcyclopent-2-en-1-one (V-24):
Figure GDA0004174641170000212
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), methyl 2-aminobenzoate (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1-phenylethane-1-one (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝10h,t 2 =17 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=15/1-10/1) gave the product V-24 as a yellow oil, 62% nuclear magnetic yield, 60% isolation yield, 4.7/1dr. HPLC analysis gave 96% ee (Chiralcel OD, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝10.4min,t r (minor)＝8.7min；[α] D 20 ＝–265.9(c＝0.96,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.08(d,J＝7.6Hz,2H),7.77(d,J＝8.0Hz,1H),7.69–7.64(m,1H),7.62(t,J＝7.7Hz,1H),7.49(t,J＝7.8Hz,2H),7.39(t,J＝7.9Hz,1H),7.25(s,1H),7.18–7.14(m,3H),7.06–6.95(m,3H),6.65–6.61(m,2H),5.69(d,J＝10.1Hz,1H),4.96(d,J＝9.1Hz,0.22H),3.61(s,3H),3.44–3.32(m,1H),3.26–3.16(m,1H). 13 C NMR(500MHz,CDCl 3 )δ8.08(d,J＝7.6Hz,2H),7.77(d,J＝8.0Hz,1H),7.69–7.64(m,1H),7.62(t,J＝7.7Hz,1H),7.49(t,J＝7.8Hz,2H),7.39(t,J＝7.9Hz,1H),7.25(s,1H),7.18–7.14(m,3H),7.06–6.95(m,3H),6.65–6.61(m,2H),5.69(d,J＝10.1Hz,1H),4.96(d,J＝9.1Hz,0.22H),3.61(s,3H),3.44–3.32(m,1H),3.26–3.16(m,1H). 19 F NMR(377MHz,CDCl 3 )δ-92.6(d,J＝276.0Hz),-96.3(d,J＝275.8Hz).HRMS(ESI)m/z calcd.For C 28 H 23 F 2 NNaO 4 [M+Na] + 498.1487,found 498.1506.
Example 25
(4R, 5R) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3- (4-methoxyphenyl) -3-oxopropyl) -5-phenylcyclopent-2-en-1-one (V-25):
Figure GDA0004174641170000221
2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1- (4-methoxyphenyl) ethane-1-one (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝14h,t 2 =16h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 The method comprises the steps of carrying out a first treatment on the surface of the The reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) to obtain yellow oily product V-25, nuclear magnetic yield 71%, separation yield 68%,>20/1dr. HPLC analysis gave 94% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝19.4min,t r (minor)＝17.0min；[α] D 20 ＝–162.0(c＝0.89,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ8.08(d,J＝8.4Hz,2H),7.67–7.59(m,1H),7.25(s,3H),7.20–7.10(m,2H),7.09–7.04(m,2H),7.01–6.88(m,3H),6.72–6.56(m,2H),5.57(d,J＝10.5Hz,1H),3.86(d,J＝2.8Hz,4H),3.44–3.28(m,1H),3.25–3.11(m,1H). 13 C NMR(126MHz,CDCl 3 )δ208.1,186.9(t,J＝29.5Hz),164.7,161.8,142.1,138.4,134.6,133.0,129.5,128.8,128.0,127.7,124.3,124.2,121.7,119.9,119.7(dd,J＝258.4,252.8Hz),118.2,114.1,113.9,111.6,59.9(d,J＝6.4Hz),57.6,55.6,38.5(t,J＝21.1Hz). 19 F NMR(377MHz,CDCl 3 )δ-92.5(d,J＝272.4Hz),-95.8(d,J＝272.6Hz).HRMS(ESI)m/z calcd.For C 27 H 22 ClF 2 NNaO 3 [M+Na] + 504.1148,found 504.1162.
Example 26
N-benzyl-3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionamide (V-26):
Figure GDA0004174641170000231
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and N-benzyl-2-bromo-2, 2-difluoroacetamide (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝12h,t 2 =43 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-4/1) to obtain yellow oily product V-26 with nuclear magnetic resonance yield of 52%, separation yield of 47%,>20/1dr. HPLC analysis gave 93% ee (Chiralcel IA, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝11.6min,t r (minor)＝10.2min；[α] D 20 ＝–30.3(c＝0.72,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.57–7.51(m,1H),7.36–7.24(m,8H),7.15(t,J＝7.9Hz,1H),7.11(d,J＝7.9Hz,1H),7.06–6.99(m,2H),6.92(d,J＝8.2Hz,1H),6.82(br,1H),6.63(t,J＝7.7Hz,1H),6.55–6.49(m,1H),5.41(d,J＝10.5Hz,1H),4.45(dd,J＝14.9,5.9Hz,1H),4.35(dd,J＝14.9,5.5Hz,1H),3.83(d,J＝10.5Hz,1H),3.35–3.19(m,1H),3.16–3.00(m,1H). 13 C NMR(126MHz,CDCl 3 )δ207.9,163.8(t,J＝28.6Hz),161.7,142.0,138.1,136.7,134.5,129.5,128.9,128.8,128.1,128.0,127.9,127.7,119.8,118.3,117.4(dd,J＝257.9,253.4Hz),111.7,60.3(d,J＝4.8Hz),57.5,43.7,39.0(t,J＝22.1Hz). 19 F NMR((377MHz,CDCl 3 )δ-97.1(d,J＝254.5Hz),-101.4(d,J＝254.6Hz).HRMS(ESI)m/z calcd.For C 27 H 23 ClF 2 N 2 NaO 2 [M+Na] + 503.1308,found 503.1326.
Example 27
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -N-cyclohexyl-2, 2-difluoropropane (27):
Figure GDA0004174641170000241
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-N-cyclohexyl-2, 2-difluoroacetamide (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝72h,t 2 =12 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow oily product V-27 with nuclear magnetic resonance yield of 36% and separation yield of 34%,>20/1dr. HPLC analysis gives 84% ee (Chiralcel ID, hexane/i-PrOH=95/5, flow rate=1.0 mL/min, l=254 nm), t r (major)＝40.1min,t r (minor)＝29.6min；[α] D 20 ＝–96.8(c＝0.84,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.58(m,1H),7.29–7.25(m,3H),7.17(t,J＝7.9Hz,1H),7.12(d,J＝7.8Hz,1H),7.08–7.03(m,2H),6.94(d,J＝8.2Hz,1H),6.64(t,J＝7.7Hz,1H),6.61–6.55(m,1H),6.18(d,J＝8.1Hz,1H),5.45(d,J＝10.6Hz,1H),3.84(d,J＝10.6Hz,1H),3.77–3.67(m,1H),3.32–3.18(m,1H),3.11–2.96(m,1H),1.94(d,J＝12.5Hz,1H),1.88(d,J＝12.4Hz,1H),1.75–1.58(m,4H),1.41–1.31(m,2H),1.22–1.16(m,2H). 13 C NMR(126MHz,CDCl 3 )δ208.0,163.0(t,J＝26.7Hz),161.7,142.0,138.2,134.6,129.4,128.7,128.0,127.9,127.7,119.8,118.2,116.3(t,J＝254.5Hz),111.7,60.2(d,J＝4.6Hz),57.5,48.8,39.0(t,J＝22.2Hz),32.6,32.5,25.3,24.6. 19 F NMR(377MHz,CDCl 3 )δ-97.6(d,J＝253.1Hz),-101.3(d,J＝253.2Hz).HRMS(ESI)m/z calcd.For C 26 H 27 ClF 2 N 2 NaO 2 [M+Na] + 495.1621,found 495.1636.
Example 28
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoro-N-phenylpropylamine (V-28):
Figure GDA0004174641170000251
2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-N-phenylacetamide (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 ＝24h,t 2 =40 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-2/1) to obtain white solid product V-28 with nuclear magnetic resonance yield of 51% and separation yield of 49%,>20/1dr. HPLC analysis gave 91% ee (Chiralcel OD, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝14.0min,t r (minor)＝12.4min；[α] D 20 ＝–130.3(c＝0.72,in CHCl 3 )；mp＝175–177℃. 1 H NMR(500MHz,DMSO)δ10.57(s,1H),7.88–7.82(m,1H),7.67(d,J＝8.0Hz,2H),7.36(t,J＝7.0Hz,2H),7.29–7.23(m,3H),7.19–7.08(m,5H),6.92(d,J＝8.2Hz,1H),6.70–6.64(m,1H),6.59(t,J＝7.7Hz,1H),5.31(d,J＝9.5Hz,1H),4.14(d,J＝9.4Hz,1H),3.50–3.37(m,1H),3.17–3.03(m,1H). 13 C NMR(126MHz,DMSO)δ207.2,162.6,161.6(t,J＝29.6Hz),141.9,138.3,137.1,134.2,129.0,128.7,128.3,128.0,127.6,127.4,124.9,121.0,118.2,117.8,111.8,117.3(t,J＝256.2Hz),60.1,56.6,37.8(t,J＝21.9Hz). 19 F NMR(377MHz,DMSO)δ-95.9(d,J＝255.6Hz),-99.2(d,J＝255.6Hz).HRMS(ESI)m/z calcd.For C 26 H 21 ClF 2 N 2 NaO 2 [M+Na] + 489.1152,found 489.1173.
Example 29
(4 r,5 r) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3-oxo-3- (piperidin-1-yl) propyl) -5-phenylcyclopent-2-en-1-one (V-29):
Figure GDA0004174641170000252
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1- (piperidin-1-yl) ethan-1-one (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝12h,t 2 =4h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1; the rest of the procedure is the same as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow oily product V-29, nuclear magnetic yield 78%, separation yield 75%,>20/1dr. HPLC analysis gave 92% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝11.7min,t r (minor)＝9.4min；[α] D 20 ＝–147.9(c＝0.94,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.58(m,1H),7.27–7.24(m,3H),7.18–7.03(m,4H),6.91(d,J＝8.1Hz,1H),6.62(t,J＝7.8Hz,1H),6.59–6.55(m,1H),5.52(d,J＝10.4Hz,1H),3.84(d,J＝10.4Hz,1H),3.64–3.51(m,4H),3.35–3.13(m,2H),1.69–1.58(m,6H). 13 C NMR(126MHz,CDCl 3 )δ208.1,161.8,161.4(t,J＝28.2Hz),142.1,138.6,134.5,129.4,128.7,128.0,127.9,127.7,119.8,119.0(dd,J＝259.1,252.6Hz),118.1,111.7,59.7(d,J＝6.4Hz),57.4,46.9(t,J＝6.0Hz),44.7,39.3(t,J＝21.4Hz),26.4,25.6,24.4. 19 F NMR(377MHz,CDCl 3 )δ-91.3(d,J＝268.4Hz),-94.8(d,J＝267.8Hz).HRMS(ESI)m/z calcd.For C 25 H 25 ClF 2 N 2 NaO 2 [M+Na] + 481.1465,found 481.1480.
Example 30
(4 r,5 r) -4- ((2-chlorophenyl) amino) -5- (2, 2-difluoro-3-morpholin-3-oxypropyl) -5-phenylcyclopent-2-en-1-one (V-30):
Figure GDA0004174641170000261
2- (1-phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-2, 2-difluoro-1-morpholone (0.4 mmol,2.0 eq) were used as reaction materials, the reaction time was t 1 ＝83h,t 2 =4h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base, 2mL dichloromethane as solvent; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=3/1-2/1) to obtain yellow oily product V-30 with nuclear magnetic resonance yield of 38% and separation yield of 36%,>20/1dr. HPLC analysis gave 89% ee (FLM Chiral NS, hexane/i-PrOH=70/30, flow rate=1.0 mL/min, l=254 nm), t r (major)＝10.4min,t r (minor)＝8.2min；[α] D 20 ＝–142.7(c＝0.71,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.63–7.58(m,1H),7.29–7.25(m,3H),7.19–7.11(m,2H),7.10–7.05(m,2H),6.90(d,J＝8.1Hz,1H),6.64(t,J＝7.7Hz,1H),6.61–6.56(m,1H),5.49(d,J＝10.5Hz,1H),3.85(d,J＝10.5Hz,1H),3.77–3.59(m,8H),3.33–3.13(m,2H). 13 C NMR(126MHz,CDCl 3 )δ208.0,161.9,161.5(t,J＝29.5Hz),142.0,138.4,134.5,129.5,128.8,128.0,128.0,127.7,119.8,118.8(dd,J＝258.8,251.8Hz),118.2,111.6,66.6,59.7(d,J＝6.0Hz),57.4,46.6(t,J＝5.6Hz),43.6,39.1(t,J＝21.4Hz). 19 F NMR(377MHz,CDCl 3 )δ-91.0(d,J＝270.3Hz),-95.0(d,J＝270.3Hz).HRMS(ESI)m/z calcd.For C 24 H 23 ClF 2 N 2 NaO 3 [M+Na] + 483.1257,found 483.1294.
Example 31
3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -N, N-diethyl-2, 2-difluoropropane (V-31):
Figure GDA0004174641170000271
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and 2-bromo-N, N-diethyl-2, 2-difluoroacetamide (0.4 mmol,2.0 eq) were used as starting materials for a reaction time t 1 ＝11h,t 2 =4h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=10/1-8/1) to obtain yellow oily product V-32 with nuclear magnetic resonance yield of 82% and separation yield of 80%,>20/1dr. HPLC analysis gave 88% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝9.0min,t r (minor)＝6.9min；[α] D 20 ＝–130.3(c＝0.92,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.56(m,1H),7.27–7.23(m,3H),7.18–7.05(m,4H),6.92(d,J＝8.2Hz,1H),6.62(t,J＝7.7Hz,1H),6.59–6.59(m,1H),5.52(d,J＝10.5Hz,1H),3.84(d,J＝10.3Hz,1H),3.51–3.32(m,4H),3.29–3.19(m,2H),1.22–1.13(m,6H). 13 C(126MHz,CDCl 3 )δ208.1,162.5(t,J＝28.4Hz),161.8,142.1,138.6,134.5,129.4,128.7,128.0,127.9,127.8,119.8,118.9(dd,J＝258.9,252.5Hz),118.1,111.7,59.6(d,J＝6.0Hz),57.4,42.1(t,J＝5.1Hz),41.9,39.5(t,J＝21.7Hz),14.3,12.3. 19 F NMR(377MHz,CDCl 3 )δ-91.8(d,J＝267.7Hz),-95.4(d,J＝267.7Hz).HRMS(ESI)m/z calcd.For C 24 H 25 ClF 2 N 2 NaO 2 [M+Na] + 469.1465,found 469.1465.
Example 32
Diethyl (2- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -1, 1-difluoroethyl) phosphonate (V-32):
Figure GDA0004174641170000281
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and diethyl (bromodifluoromethyl) phosphonate (0.4 mmol,2.0 eq) were used as starting materials, the reaction time was t 1 ＝96h,t 2 =15 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 The procedure of example 1 was followed by purification by silica gel column chromatography (petroleum ether/ethyl acetate=8/1-6/1) to give product V-32 as a yellow oil in a nuclear magnetic resonance yield of 55%, isolation yield of 53%,>20/1dr. HPLC analysis gave 87% ee (FLM Chiral INB, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝13.8min,t r (minor)＝7.5min；[α] D 20 ＝–87.9(c＝0.79,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.60–7.56(m,1H),7.26(s,2H),7.19–7.10(m,2H),7.07–7.01(m,2H),6.93(d,J＝8.3Hz,1H),6.68–6.56(m,2H),5.50(d,J＝10.5Hz,1H),4.45–4.22(m,4H),3.82(d,J＝10.6Hz,1H),3.29–3.01(m,2H),1.44–1.36(m,6H),1.35–1.23(m,1H). 13 C NMR(126MHz,CDCl 3 )δ207.7,161.3,142.1,138.2,134.4,129.5,128.8,125.1(dt,J＝255.8,212.9Hz),119.8,118.2,111.6,65.0(dd,J＝17.9,6.8Hz),59.9,59.8,57.4,57.3,38.1(q,J＝18.6,17.8Hz),16.4,16.4. 19 F NMR(377MHz,CDCl 3 )δ-102.9(dd,J＝295.5,110.3Hz),-107.6(dd,J＝295.7,101.5Hz).HRMS(ESI)m/z calcd.For C 23 H 25 ClF 2 NNaO 4 P[M+Na] + 506.1070,found506.1101.
Example 33
(3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoroalkyl) -L-phenylalanine ethyl ester (V-33):
Figure GDA0004174641170000291
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and ethyl (2-bromo-2, 2-difluoroacetyl) -L-phenylpropionate (0.4 mmol,1.0 eq) were used as starting materials, the reaction time was t 1 ＝34h,t 2 =16h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=6/1-5/1) to obtain yellow oily product V-33, nuclear magnetic resonance yield 45%, separation yield 43%,>20/1syn: anti. HPLC analysis gave 89% de (Chiralcel IA, hexane/i-PrOH=80/20, flow rate=1.0 mL/min, l=254 nm), t r (major)＝9.0min,t r (minor)＝10.7min；[α] D 20 ＝–66.7(c＝0.91,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.59–7.55(m,1H),7.28–7.22(m,5H),7.20–7.14(m,2H),7.11(d,J＝7.7Hz,3H),7.05–7.00(m,2H),6.89(d,J＝8.3Hz,1H),6.83(d,J＝8.1Hz,1H),6.63(t,J＝7.7Hz,1H),6.60–6.56(m,1H),5.38(d,J＝10.7Hz,1H),4.82(q,J＝6.9Hz,1H),4.20(q,J＝7.5Hz,2H),3.83(d,J＝10.5Hz,1H),3.21–3.04(m,3H),3.02–2.90(m,1H),1.25(t,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.7,170.4,163.3(t,J＝29.4Hz),161.5,142.0,138.2,135.1,134.6,129.4,129.4,128.7,128.0,128.0,127.7,127.4,119.8,118.2,117.2(t,J＝253.9Hz),111.7,61.9,60.0(d,J＝4.9Hz),57.3,53.2,38.8(t,J＝21.7Hz),37.8,14.1. 19 F NMR(377MHz,CDCl 3 )δ-98.4(d,J＝255.1Hz),-101.8(d,J＝255.0Hz).HRMS(ESI)m/z calcd.For C 31 H 29 ClF 2 N 2 NaO 4 [M+Na] + 589.1676,found 589.1697.
Example 34
(1 s,2r,5 s) -2-isopropyl-5-methylcyclohexyl 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate (V-34):
Figure GDA0004174641170000292
2- (1-Phenylvinyl) furan (0.24 mmol,1.2 eq), 2-chloroaniline (0.2 mmol,1.0 eq) and (1S, 2R, 5S) -2-isopropyl-5-methylcyclohexyl 2-bromo-2, 2-difluoroacetic acid (0.4 mmol,2.0 eq) were used as starting materials for reaction for a period of time t 1 ＝20h,t 2 =24 h, the photocatalyst used in step 1 was 2mol% mer-Ir (ppy) 3 ,NaHCO 3 (0.6 mmol,3.0 eq) as base; the reaction solvent used in step 2 was 4mL chloroform, and the catalyst amount was 2mol% Dy (OTf) 3 And 6mol% A1, the remainder of the procedure being as in example 1. Purifying by silica gel column chromatography (petroleum ether/ethyl acetate=20/1-15/1) to obtain yellow oily product V-34 with nuclear magnetic resonance yield of 61% and isolation yield of 59%,>20/1syn: anti. HPLC analysis gave 94% de (Chiralcel ID, hexane/i-PrOH=90/10, flow rate=1.0 mL/min, l=254 nm), t r (major)＝5.7min,t r (minor)＝7.1min；[α] D 20 ＝–110.8(c＝0.97,in CHCl 3 ). 1 H NMR(500MHz,CDCl 3 )δ7.62–7.54(m,1H),7.31–7.26(m,3H),7.20–7.11(m,2H),7.08–7.02(m,2H),6.90(d,J＝8.1Hz,1H),6.64(t,J＝7.8Hz,1H),6.60–6.56(m,1H),5.45(d,J＝10.3Hz,1H),4.86–4.76(m,1H),3.82(d,J＝10.5Hz,1H),3.26–3.01(m,2H),2.08(d,J＝12.2Hz,1H),1.91–1.81(m,1H),1.72–1.65(m,2H),1.54–1.45(m,2H),1.14–1.01(m,2H),0.96–0.86(m,7H),0.75(d,J＝7.0Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ207.3,163.1(t,J＝32.2Hz),161.5,142.0,138.4,134.6,129.5,128.8,128.0,127.7,119.9,118.2,115.8(dd,J＝255.6Hz,255.6Hz),111.5,78.1,59.8(d,J＝3.7Hz),57.3,46.8,40.2,38.8(t,J＝21.6Hz),34.0,31.5,26.2,23.4,22.0,20.7,16.2. 19 F NMR(377MHz,CDCl 3 )δ-96.1(d,J＝261.6Hz),-101.9(d,J＝261.6Hz).HRMS(ESI)m/z calcd.For C 30 H 34 ClF 2 NNaO 3 [M+Na] + 552.2087,found 552.2117.
Expansion experiments of the invention
Synthetic route for 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionic acid ethyl ester (V-1):
Figure GDA0004174641170000301
step 1, photo-catalyst mer-Ir (ppy) 3 (19.5 mg,0.03 mmol) and K 2 CO 3 (829.5 mg,6.0mmol,2.0 eq) was placed in a reaction tube and a magnetic stirrer of suitable size was placed. Vacuum drying, replacing three times with argon, and adding 30mL of acetonitrile under the protection of argon. 2- (1-Phenylvinyl) furan (612 mg,3.6mmol,1.2 eq), o-chloroaniline (762 mg,3.0mmol,1.0 eq) and ethyl 2-bromo-2, 2-difluoroacetate (1.22 g,6.0mmol,2.0 eq) were then added in sequence. The reaction mixture was degassed with argon for 10 minutes and then reacted at room temperature under irradiation of a blue LED lamp with a power of 3W, and the reaction was monitored by TLC. When TLC showed complete conversion of arylamine compounds (t 1 =60 h), the reaction mixture was filtered through celite, washed with dichloromethane and concentrated to give crude intermediate IV which was used directly in the next step.
Step 2 Dy (OTf) 3 (36 mg,0.06 mol) and Bronsted acid A1 (64.8 mg,0.072 mmol). Placing the mixture in a reaction tube, and placing a magnetic stirrer with proper size. Vacuum drying, three times with argon substitution, adding chloroform (5.0 mL) under argon protection and stirring at room temperature for 1 min. Subsequently, intermediate IV obtained in step 1 was dissolved in chloroform (15.0 mL) and added to the reaction mixture to react at room temperature. After completion of the reaction (t 2 =48 h), the reaction solution was concentrated and separated by silica gel column chromatography (petroleum ether/ethyl acetate=20/1-15/1) to give 0.9g of ethyl 3- ((1 r,2 r) -2- ((2-chlorophenyl) amino) -5-oxo-1-phenylcyclopent-3-en-1-yl) -2, 2-difluoropropionate as a product in an isolation yield of 70%.
Drawings
FIG. 1 shows the chemical formula of the technical scheme adopted by the invention
FIG. 2 is a structural formula of a series of difluoroalkyl group containing chiral multi-functional cyclopentenone derivatives
The raw material sources used for each of the above chemical reactions are listed below:
reagent name CAS number Purity of Specification of specification Manufacturer' s
Potassium carbonate 584-08-7 AR 500g Color-dawn
Dysprosium triflate 139177-62-1 98％ 25g Adamas
Trichloromethane 887144-97-0 98％ 5g Bi De medicine
Acetonitrile 75-05-8 AR 500mL Color-dawn
Petroleum ether 8032-32-4 AR 15kg Color-dawn
Acetic acid ethyl ester 141-78-6 AR 20kg Color-dawn
Dichloromethane (dichloromethane) 75-09-2 AR 25kg Color-dawn

Claims (8)

1. A process for the asymmetric synthesis of a difluoroalkyl group containing polyfunctional cyclopentenone derivative, comprising the steps of:
step S1 is a free radical-mediated three-component difluoroalkylation amination reaction which is carried out by taking furan alkene, aromatic amine compound and difluoroalkyl halide as raw materials under visible light, wherein the reaction formula is as follows:
Figure FDA0004166639490000011
step S2, taking an intermediate IV, adding chiral Bronsted acid and achiral Lewis acid, and carrying out asymmetric rearrangement reaction in an organic solvent to obtain a product V, wherein the reaction formula is as follows:
Figure FDA0004166639490000012
wherein the method comprises the steps of
R is phenyl, 2-naphthyl or benzene ring containing substituent, and the substituent on the benzene ring is one of methyl, methoxy or halogen;
R 1 is H or methyl;
ar is benzene ring connected with different groups of electron withdrawing or electron donating, wherein the different groups are one or two of methyl, methoxy, halogen, ester, trifluoromethyl, benzoyl or acetyl;
R F the raw material of the difluoromethylene with different groups is difluoroalkyl halide III selected from one of the following compounds:
Figure FDA0004166639490000013
the photocatalyst described in step S1 is mer-Ir (ppy) 3 The alkali is potassium carbonate, and the reaction temperature is room temperature;
the visible light in the step S1 is provided by a blue LED lamp with the power of 3W and the wavelength of 460-465 nm;
the achiral Lewis acid in the step S2 is dysprosium triflate, and the reaction temperature is room temperature;
the chiral bronsted acid in step S2 has the following structural formula:
Figure FDA0004166639490000021
2. the method of claim 1, wherein: the dosage ratio of furan alkene, aromatic amine compound and difluoroalkyl halide in the reaction of step S1 is 0.24mmol:0.20mmol:0.40mmol.
3. The method of claim 1, wherein: mer-Ir (ppy) in step S1 reaction 3 The molar amount of the potassium carbonate and the aromatic amine compound is 0.33 percent, and the molar amount ratio of the potassium carbonate to the aromatic amine compound is 0.4mmol to 0.20mmol.
4. The method of claim 1, wherein: step S1 reaction time t 1 10-96h.
5. The method of claim 1, wherein: the organic solvent in the reaction in the step S1 is acetonitrile, the ratio of the amount of the substance of the arylamine compound to the volume of the acetonitrile is 0.1 mmol/2 mL, and the reaction is carried out under the argon atmosphere.
6. The method of claim 1, wherein: the visible light in the reaction of step S1 was provided by a blue LED lamp with a power of 3W and a wavelength of 460-465nm, the distance between the blue lamp and the reactant being 4cm.
7. The method of claim 1, wherein: dy (OTf) in step S2 reaction 3 The molar dosage of the chiral Bronsted acid A1 is 0.33 percent and 1 percent of that of the arylamine compound respectively.
8. The method of claim 1, wherein: the organic solvent in the step S2 reaction is chloroform, the solvent dosage is 2mL, and the reaction time t 2 3-120h.
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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Guanglong Pan 等.Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds .《Beilstein J. Org. Chem.》.2021,第17卷第 1171-1180 页. *
Huilin Li 等.Catalytic Enantioselective Aza-Piancatelli Rearrangement.《Angew. Chem. Int. Ed.》.2016,第55卷第 15125-15 128 页. *
Lei Xu 等.Ln(III)/Chiral Brønsted Acid catalyzed Asymmetric Cascade Ring Opening/Aza-Piancatelli Rearrangement of D-A Cyclopropanes.《Org. Lett.》.2020,第22卷第 9016-902 1 页. *
Yunfei Cai 等.Catalytic Asymmetric Piancatelli Rearrangement: Brønsted Acid Catalyzed 4p Electrocyclization for the Synthesis of Multisubstituted Cyclopentenones.《Angew. Chem. Int. Ed.》.2016,第55卷第 14126-14 130 页. *

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