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Asymmetric synthesis method of trifluoromethyl-containing multifunctional cyclopentenone derivative

A technology of trifluoromethyl and cyclopentenone, applied in the field of asymmetric synthesis of polyfunctionalized cyclopentenone derivatives, achieves mild reaction conditions, high chemical yield, enantioselectivity and diastereoselectivity Excellent effect

Active Publication Date: 2021-10-15
CHONGQING UNIV
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  • Abstract
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Problems solved by technology

At present, there is no relevant literature report on the method of introducing trifluoromethyl group into the side chain of cyclopentenone

Method used

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  • Asymmetric synthesis method of trifluoromethyl-containing multifunctional cyclopentenone derivative
  • Asymmetric synthesis method of trifluoromethyl-containing multifunctional cyclopentenone derivative
  • Asymmetric synthesis method of trifluoromethyl-containing multifunctional cyclopentenone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (4R,5R)-4-((2-chlorophenyl)amino)-5-phenyl-5-(2,2,2-trifluoroethyl)cyclopent-2-ene-1- The synthetic route of ketones:

[0027]

[0028] The reaction catalyst CuCl (0.5mg, 0.005mmol), Dy (OTf) 3 (1.2mg, 0.002mmol) and Bronsted acid A1 (5.4mg, 0.006mmol) were placed in a reaction tube, and a magnetic stir bar of appropriate size was placed. Vacuum-dried, replaced with argon three times, and added 4 mL of chloroform under the protection of argon. The reaction was then cooled to 0°C, and Togni reagent 3a (49.5mg, 0.15mmol), o-chloroaniline (0.10mmol, 1.0eq) and 2-(1-phenylvinyl)furan (0.15mmol, 1.5eq) were added sequentially ). The temperature was raised to 45°C and stirred at this temperature, the reaction was monitored by TLC. After the reaction was completed, after flash column chromatography, 1,3,5-trimethoxybenzene was used as an internal standard to carry out 1 H NMR characterization to determine the NMR yield and dr value of the product. The crude product wa...

Embodiment 2

[0032] (4R,5R)-4-((2-Chlorophenyl)amino)-5-(4-tolyl-5-(2,2,2-trifluoroethyl)cyclopent-2-ene-1- Ketones (2):

[0033]

[0034] With 2-(1-(p-tolyl)vinyl)furan (0.15mmol, 1.5eq), 2-chloroaniline (0.1mmol, 1.0eq) and Togni reagent 3a (49.5mg, 0.15mmol) as the reaction raw materials, the rest Operation is with embodiment 1. After reacting for 12 hours, it was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1–15 / 1) to obtain product 2 in the form of yellow oil, with a NMR yield of 90%, an isolation yield of 83%, and >20 / 1dr . HPLC analysis yielded 92%ee (Chiralcel OD, hexane / i-PrOH=90 / 10, flow rate=1.0mL / min, l=254nm), t r (major) = 8.0 min, t r (minor) = 6.2min; [α] D 20 =–112.5 (c=0.97, in CHCl 3 ). 1 H NMR (500MHz, CDCl 3 )δ7.66–7.56(m,1H),7.20–7.12(m,2H),7.08(d,J=7.8Hz,2H),6.90(d,J=8.4Hz,2H),6.85(d,J =8.2Hz,1H),6.65(t,J=7.5Hz,1H),6.62–6.57(m,1H),5.27(d,J=10.4Hz,1H),3.88(d,J=10.4Hz,1H ),3.24–3.05(m,2H),2.30(s,3H). 13 C NMR (126MHz, CD...

Embodiment 3

[0036] (4R,5R)-5-([1,1'-biphenyl)-4-yl)-4-((2-chlorophenyl)amino)-5-(2,2,2-trifluoroethane Base) cyclopent-2-en-1-one (3):

[0037]

[0038] With 2-(1-(p-tolyl)vinyl)furan (0.15mmol, 1.5eq), 2-chloroaniline (0.1mmol, 1.0eq) and Togni reagent 3a (49.5mg, 0.15mmol) as the reaction raw materials, the rest Operation is with embodiment 1. After reacting for 24 hours, it was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1–15 / 1) to obtain the product 3 as a white solid, with a NMR yield of 87%, an isolation yield of 82%, and >20 / 1dr . HPLC analysis yielded 93%ee (FLM Chiral INB, hexane / i-PrOH=90 / 10, flow rate=1.0mL / min, l=254nm), t r (major)=42.1min,t r (minor) = 9.9min; [α] D 20 =–29.2 (c=0.97, in CHCl 3 ); mp=138–140°C. 1 H NMR (500MHz, CDCl 3 )δ7.68–7.62(m,1H),7.52(d,J=7.5Hz,2H),7.47(d,J=7.0Hz,2H),7.43(t,J=7.5Hz,2H),7.35( t,J=7.5Hz,1H),7.18(t,J=8.0Hz,1H),7.13(d,J=7.2Hz,1H),7.06(d,J=7.1Hz,2H),6.88(d, J=8.2Hz, 1H), 6.69–6.63(m, 2H), 5.3...

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Abstract

The invention provides a method for asymmetrically synthesizing a trifluoromethyl-containing multifunctional cyclopentenone derivative. According to the method, cuprous, chiral Bronsted acid and achiral Lewis acid are taken as a combined catalyst, furan olefin, a Togni reagent and an arylamine compound are taken as raw materials, and an asymmetric three-component aza-Piancatelli rearrangement reaction is carried out, so that the trifluoromethyl-containing chiral multifunctional cyclopentenone derivative is prepared. The method has the advantages of mild reaction conditions, excellent enantioselectivity and diastereoselectivity, high chemical yield and potential practical application value.

Description

technical field [0001] The invention belongs to the field of asymmetric synthesis in organic chemistry, and in particular relates to an asymmetric synthesis method of trifluoromethyl-containing polyfunctional cyclopentenone derivatives. Background technique [0002] Chiral multifunctional cyclopentenone is an extremely important class of small organic molecules, which can not only be used as key intermediates in medicine, but also have a wide range of physiological activities, and are also the core skeleton of many natural products. The furyloxonium ion-directed asymmetric rearrangement reaction is an efficient method to construct such compounds, but it is currently limited to the two-component rearrangement reaction based on furfuryl alcohol substrates, which limits the functional group compatibility of this type of reaction and the Applications in Symmetrical Synthesis. In medicinal chemistry, compounds containing trifluoromethyl groups have significant physiological acti...

Claims

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Application Information

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IPC IPC(8): C07C221/00C07C225/20
CPCC07C221/00C07C225/20
Inventor 蔡云飞徐磊杨倩
Owner CHONGQING UNIV
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