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3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and synthetic method thereof

A technology of carboxy indole derivatives and difluoroalkyl, which is applied in the field of all-carbon quaternary carboxy indole derivatives and their synthesis, and achieves the effects of high yield and enantioselectivity, wide application range and mild reaction conditions

Active Publication Date: 2014-10-15
EAST CHINA NORMAL UNIVERSITY
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  • Application Information

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Problems solved by technology

However, there is still no report on the 3-position all-carbon quaternary carbooxindole derivative skeleton containing C3-difluoroalkyl substitution. In comparison, the synthesis of such compounds is more challenging

Method used

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  • 3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and synthetic method thereof
  • 3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and synthetic method thereof
  • 3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and synthetic method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of 3-difluoroalkyl-substituted oxindole III-1:

[0041]

[0042] In a 5.0mL reaction flask, add dinitrile-substituted alkenyl oxide indole I-1 (48.8mg, 0.25mmol), phenyl-substituted difluoroenolsilyl ether II-1 (570mg, 2.5mmol), distilled water (5.0 mL), the reaction solution was stirred at 50° C. for 15 h. TLC detects that the raw materials have basically reacted, and the reaction is stopped. The reaction solution was extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, transferred to a 50mL round-bottomed flask, added about 1.0g of crude silica gel, spin-dried and then column chromatographed, eluent (ethyl acetate / petroleum ether=1 / 3), the product III-1 was obtained as light yellow solid 80.1mg, and the yield was 90%. 1 H NMR (400MHz, CDCl 3 ):δ8.49(s,1H),8.02-8.00(m,2H),7.68-7.64(m,2H),7.50-7.42(m,3H),7.18-7.14(m,1H),7.06-7.04 (m,1H),4.92(s,1H); 13 C NMR (100MHz, CDCl 3 ): δ185.3(t, J=30Hz, 1C), 170.5(d, J=8Hz, 1C), 141.7, 13...

Embodiment 2

[0044] Synthesis of 3-difluoroalkyl-substituted oxindole III-2:

[0045]

[0046] Add benzoic acid (3.1mg, 0.025mmol), dinitrile-substituted alkenyl oxide indole I-2 (53.3mg, 0.25mmol) and phenyl-substituted difluoroenolsilyl ether II to a 5.0mL reaction flask in sequence -1 (85.5mg, 0.375mmol), tetrahydrofuran (3.0mL); the reaction solution was stirred at room temperature for 5h. TLC detects that the raw material has basically reacted completely, and the reaction is stopped. Transfer the reaction solution to a 50mL round-bottomed flask, drain the solvent under the oil pump, perform direct column chromatography, eluent (ethyl acetate / petroleum ether=1 / 3), and obtain product III-2 as a light yellow solid 85.8 mg, yield 93%. 1 H NMR (400MHz, CDCl 3 ):δ8.34(s,1H),8.03-8.01(m,2H),7.71-7.67(m,1H),7.52-7.49(m,2H),7.43-7.42(m,1H),7.20-7.15 (m,1H),7.04-7.01(m,1H),4.90(s,1H); 13 C NMR (100MHz, CDCl 3 ): δ185.2(t, J=31Hz, 1C), 170.5(d, J=8Hz, 1C), 159.2(d, J=243Hz, 1C), 137.8(d...

Embodiment 3

[0048] Synthesis of 3-difluoroalkyl-substituted oxindole III-3:

[0049]

[0050] Add Cu(OTf) sequentially to the 5.0mL reaction flask 2 (4.5mg, 0.0125mmol), dinitrile substituted alkenyl oxide indole I-3 (52.3mg, 0.25mmol), phenyl substituted difluoroenol silyl ether II-1 (62.7mg, 0.275mmol), Anhydrous ether (2.0 mL); the reaction solution was stirred at room temperature for 3 h. TLC detects that the raw material has basically reacted completely, and the reaction is stopped. Transfer the reaction solution to a 50mL round-bottomed flask, drain the solvent under the oil pump, perform direct column chromatography, eluent (ethyl acetate / petroleum ether=1 / 3), and obtain product III-3 as a light yellow solid 77.6 mg, yield 85%. 1 H NMR (400MHz, CDCl 3 ):δ8.14(s,br,1H),8.03-8.01(m,2H),7.68-7.65(m,1H),7.51-7.47(m,3H),7.25-7.24(m,1H),6.95 -6.93(m,1H),4.89(s,1H),2.35(s,3H); 13 C NMR (100MHz, CDCl 3 ): δ185.4(t, J=31Hz, 1C), 170.4, 139.2, 135.4, 133.8, 132.4, 130.4(t, J=3Hz, 1...

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Abstract

The invention discloses a 3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and a synthetic method thereof. The structure of the compound is in the formula (refer to the Specification); the compound has underlying biological activities and pharmacological activities; formidable technical supports are provided for the development of new medicines and the high utility value is achieved. According to the synthetic method of the compound, alkene derivative of isatin and a nucleophilic reagent difluoro-silyl enol ether are taken as raw materials, subjected to a Mukaiyama-Michael additive reaction and synthesized in one step. The method has the characteristics that the raw materials are cheap and easy to get, the reaction conditions are mild, the operation is convenient, the application range of substrates is broad and the excellent productivity and enantioselectivity can be acquired and the like.

Description

technical field [0001] The invention belongs to the technical field of organic compounds, and relates to the synthesis of 3-difluoroalkyl substituted all-carbon quaternary carbooxindole derivatives starting from difluoroenol silyl ether and isatin-derived olefins and a synthesis method thereof. Background technique [0002] 3,3-disubstituted oxindole with a C3 quaternary carbon center (as shown in the following formula (1)) widely exists in natural product molecules, drug molecules, drug candidates and lead compounds of new drugs [(1) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381. (2) Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 327.]. At the same time, this kind of compound is also a very useful synthetic building block, which is widely used in the total synthesis research of other related natural products with strong biological activity. Therefore, the 3,3-disubstituted oxindole skeleton has very high application value in organic synthesis...

Claims

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Application Information

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IPC IPC(8): C07D209/34
CPCY02P20/55C07D209/34
Inventor 周剑余金生
Owner EAST CHINA NORMAL UNIVERSITY
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