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Chiral 2,3-dihydrobenzofuran derivative and preparation method thereof

A technology of furan derivatives and dihydrobenzene, applied in the field of chiral 2,3-dihydrobenzofuran derivatives and its preparation, achieving the effects of convenient operation, environmental friendliness, and simple synthesis method

Active Publication Date: 2019-04-19
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these reactions are for the construction of racemates, and there is no report on the one-step asymmetric synthesis of chiral 2,3-dihydrobenzofuran derivatives

Method used

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  • Chiral 2,3-dihydrobenzofuran derivative and preparation method thereof
  • Chiral 2,3-dihydrobenzofuran derivative and preparation method thereof
  • Chiral 2,3-dihydrobenzofuran derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] ((2s,3s)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (1a-1 ) preparation:

[0054]

[0055] Add 31.0mg of compound 2a (0.1mmol) and 24mg of compound 3a (0.12mmol), 15.2mg (0.15mmol) of triethylamine, catalyst 4d (0.01mmol) and 1mL of acetonitrile into the reaction flask, stir and mix well at 30°C The reaction occurs below. The reaction catalyst loading was 5mol%, and the reaction was 6h. TLC showed that the raw material 2a was completely consumed, and direct concentration column chromatography (petroleum ether / ethyl acetate, v / v=40 / 1) gave 46.8 mg of product 1a-1, which Single crystal structure see figure 1 ; Yield 96%, 97%ee, >99:1dr.

[0056] NMR and MS data: 1 H NMR (400MHz, CDCl 3 )δ7.93(d, J=7.2Hz, 2H), 7.59(dd, J=7.6, 7.2Hz, 1H), 7.44(dd, J=8.0, 7.6Hz, 2H), 7.20(dd, J=8.0 ,7.6Hz,1H),7.04(d,J=7.2Hz,1H),6.98(d,J=8.0Hz,1H),6.94(s,2H),6.90(dd,J=7.6,7.2Hz,1H ), 5.77(d, J=6.4Hz, 1H), 5.17(s, 1H), 4.85(d, J=6.4Hz, 1H), 1.3...

Embodiment 2

[0058] ((2s,3s)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methyl-2,3-dihydrobenzofuran-2-yl)(phenyl)methyl Preparation of ketone (1a-2):

[0059]

[0060] Add 32.4mg of compound 2b (0.1mmol) and 24mg of compound 3a (0.12mmol), 15.2mg (0.15mmol) of triethylamine, catalyst 4e (0.01mmol) and 1mL of acetonitrile into the reaction flask, stir and mix with 30°C A [4+1] cycloaddition reaction occurs. The reaction catalyst loading is 5mol%, reacted for 4h, TLC showed that the raw material 2b was completely consumed, and directly concentrated column chromatography (petroleum ether / ethyl acetate, v / v=30 / 1) to obtain 45.0 mg of product 1a-2. Rate 93%, 99% ee, >99:1dr.

[0061] NMR and MS data: 1 H NMR (400MHz, CDCl 3 )δ7.91(d, J=7.2Hz, 2H), 7.58(dd, J=7.6, 7.2Hz, 1H), 7.43(dd, J=8.0, 7.6Hz, 2H), 6.99(d, J=7.6 Hz,1H),6.95(s,2H),6.86(d,J=8.4Hz,2H),5.75(d,J=6.8Hz,1H),5.17(s,1H),4.79(d,J=6.8 Hz,1H),2.24(s,3H),1.39(s,18H); 13 C NMR (101MHz, CDCl 3 )δ195.50,157.29,153.17,136.38,134.77...

Embodiment 3

[0063] ((2s 3s)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-7fluoro-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (1a -3) Preparation:

[0064]

[0065] Add 32.8mg of compound 2c (0.1mmol) and 24mg of compound 3a (0.12mmol), 15.2mg (0.15mmol) of triethylamine, catalyst 4e (0.01mmol) and 1mL of acetonitrile into the reaction flask, stir and mix well with 20°C A [4+1] cycloaddition reaction occurs. The reaction catalyst loading is 5mol%. After 6 hours of reaction, TLC showed that the raw material 2c was completely consumed. Direct concentration and column chromatography (petroleum ether / ethyl acetate, v / v=20 / 1) gave 42.0 mg of product 1a-3. Rate 94%, 99% ee, >99:1dr.

[0066] NMR and MS data: 1 H NMR (400MHz, CDCl 3 )δ7.96(d, J=7.2, Hz, 2H), 7.61(dd, J=7.6, 7.2Hz, 1H), 7.46(dd, J=8.0, 7.6Hz, 2H), 7.03-6.97(m, 1H),6.95(s,2H),6.88-6.80(m,2H),5.86(d,J=6.8Hz,1H),5.20(s,1H),4.95(d,J=6.8Hz,1H), 1.39(s,18H); 13 C NMR (101MHz, CDCl 3 )δ194.43, 153.34, 148.83, 146.38, 145.96 (d, J C...

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Abstract

The invention provides a chiral 2,3-dihydrobenzofuran derivative and a preparation method thereof. The preparation method comprises the steps that a para-position quinine methyl (p-QMs) and carbonyl compound, a chiral quaternary phosphonium salt catalyst and alkali are uniformly stirred in a solvent, stirring is carried out for 3-72 h at -78-40 DEG C, a [4+1] cycloaddition reaction is carried out,and the chiral 2,3-dihydrobenzofuran derivative is obtained through treatment. The chiral 2,3-dihydrobenzofuran derivative and the preparation method thereof have the advantages that the reaction conditions are mild, the chiral 2,3-dihydrobenzofuran derivative is green and environmentally friendly, the reaction yield is high, and the stereoselectivity is high; the obtained product is a core framework of multiple natural product molecules and chiral drug molecules with important biological activity, and has very strong application value.

Description

technical field [0001] The invention belongs to the technical field of chemical industry, and in particular relates to a chiral 2,3-dihydrobenzofuran derivative and a preparation method thereof. Background technique [0002] 2,3-Dihydrobenzofuran derivatives (2,3-Dihydrobenzofuran derivatives) are a very important class of drug molecule fragments, which widely exist in natural products and bioactive drug molecules, such as (+)-conocarpan is widely used Insecticides and antifungal agents; Obtusafuran is a quinone reductase, has anti-multidrug resistance; Stachybotrylactam can be widely used as an HIV-1 enzyme inhibitor, 2,3-dihydrobenzofuran skeleton Also an important backbone component in DNA topoisomerase II. Many of its important chiral drug molecules contain 2,3-dihydrobenzofuran skeletons, so the development of efficient methods for the construction of chiral chiral 2,3-dihydrobenzofuran structures has become an important issue in the field of synthetic chemistry resear...

Claims

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Application Information

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IPC IPC(8): C07D307/80C07D409/06C07D493/10C07D307/94C07D333/56
CPCC07B2200/07C07D307/80C07D307/94C07D333/56C07D409/06C07D493/10
Inventor 王天利谭建平陈源蒋智玉
Owner SICHUAN UNIV
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