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Chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile derivative and preparation method thereof

A dicarbonyl and aryl spiro technology, applied in the field of asymmetric catalysis, can solve the problems of chiral spiro rings that have not been reported in the literature, and achieve the effects of excellent diastereoselectivity, high conversion frequency, and excellent enantioselectivity

Inactive Publication Date: 2012-05-02
SUZHOU UNIV
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  • Abstract
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Problems solved by technology

[0014] Although there are many reported synthetic spirocyclic oxindole compounds, it has been found through literature review that no literature has reported chiral spiro[cyclohexane-1,3'-indole]-2',3-dione Synthesis of [s piro[cyclohexane-1,3′-indoline]-2′,3-diones] skeleton compound

Method used

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  • Chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile derivative and preparation method thereof
  • Chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile derivative and preparation method thereof
  • Chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile derivative and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047]

[0048] Quinidine I (6.5mg, 0.02mmol), additive A1 (4.9mg, 0.04mmol) and 2a (29.2mg, 0.2mmol) and 1a (19.5mg, 0.1mmol) were loaded into the reaction flask successively, and 1mL of 1 , 2-dichloroethane, reacted at room temperature for 42 hours, the reaction system was extracted with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed, and the crude product was subjected to simple column chromatography (eluent was ethyl acetate Ester:petroleum ether=1:3) to obtain the target product 3a (29.0 mg) with a yield of 85%.

[0049] The product was analyzed and the results were as follows: 16:84dr, 99%ee. Measured by HPLC [Daicel Chiralpak AD-H, hexane / i-PrOH=80:20, λ=254nm, flow rate 1.0mL / min]: tR=14.059 min(secondary); tR=14.973min(primary). 1 H NMR (300MHz, DMSO-d 6 )δ11.30(s, 1H), 7.51-7.40(m, 7H), 7.10(t, J=9.0Hz, 1H), 7.03(d, J=6.0Hz, 1H), 4.30(dd, J=12.0 , 3.0Hz, 1H), 3.58(t, J=15.0Hz, 1H), 3.25(d, J=15.0Hz, 1H), 2....

Embodiment 2

[0051]

[0052] Load quinidine I (6.5mg, 0.02mmol) successively in the reaction bottle, additive A2 (6.7mg, 0.04mmol) and 2a (29.2mg, 0.2mmol), 1a (19.5mg, 0.1mmol), add 1mL 1 , 2-dichloroethane, reacted at 80°C for 7 hours, the reaction system was extracted with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate, and the solvent was removed, and the crude product was subjected to simple column chromatography (eluent was acetic acid Ethyl ester:petroleum ether=1:3) to obtain the target product 3a (31.4 mg) with a yield of 92%.

[0053] The product was analyzed and the results were as follows: 17:83dr, 90%ee. Measured by HPLC [Daicel Chiralpak AD-H, hexane / i-PrOH=80:20, λ=254nm, flow rate 1.0mL / min]: t R =14.059min (times); t R =14.973min(main). 1 H NMR (300MHz, DMSO-d 6 )δ11.30(s, 1H), 7.51-7.40(m, 7H), 7.10(t, J=9.0Hz, 1H), 7.03(d, J=6.0Hz, 1H), 4.30(dd, J=12.0 , 3.0Hz, 1H), 3.58(t, J=15.0Hz, 1H), 3.25(d, J=15.0Hz, 1H), 2.82(dd, J=12.0, 3.0Hz, 1H)...

Embodiment 3

[0055]

[0056]In the reaction bottle, load quinidine I (6.5mg, 0.02mmol) successively, additive A3 (4.6mg, 0.04mmol) and 2a (29.2mg, 0.2mmol), 1a (19.5mg, 0.1mmol), add 1mL 1 , 2-dichloroethane, reacted at room temperature for 96 hours, the reaction system was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed, and the crude product was subjected to simple column chromatography (eluent was ethyl acetate Ester:petroleum ether=1:3) to obtain the target product 3a (29.0 mg) with a yield of 85%.

[0057] The product was analyzed and the results were as follows: 93:7dr, 92%ee. Measured by HPLC [Daicel Chiralpak AD-H, hexane / i-PrOH=80:20, λ=254nm, flow rate 1.0mL / min]: t R =14.059min (times); t R =14.973min(main). 1 H NMR (300MHz, DMSO-d 6 )δ11.30(s, 1H), 7.51-7.40(m, 7H), 7.10(t, J=9.0Hz, 1H), 7.03(d, J=6.0Hz, 1H), 4.30(dd, J=12.0 , 3.0Hz, 1H), 3.58(t, J=15.0Hz, 1H), 3.25(d, J=15.0Hz, 1H), 2.82(dd, J=12.0, 3....

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Abstract

The invention belongs to the field of asymmetric catalysis, and specifically relates to a method for synthesizing a novel chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile compound. According to the invention, chiral primary amine derived from quinine is adopted as a catalyst, and chiral or achiral Brownst acid is adopted as a co-catalyst, such that the compound is synthesized under catalyzing. According to the invention, the chiral 2',5-dicarbonyl-3-aryl spiro[cyclohexane-1,3'-indole]-2,2-dinitrile compound is synthesized through a dual-Michael addition reaction of an isatin malononitrile condensation substance and methyl aryl alpha,beta-unsaturated ketone. The synthesizing method is advantaged in simple raw materials which are easy to acquire, convenient operation, and good substrate compatibility. A plurality of chiral centers can be established with a one-kettle method. Under a high-temperature reaction condition, high yield and high conversion frequency are realized, and excellent enantioselectivity and excellent diastereoselectivity can be realized.

Description

technical field [0001] The invention belongs to the field of asymmetric catalysis, and in particular relates to a co-catalyzed preparation of chiral 2′,5-dicarbonyl-3-arylspiro[cyclohexane-1,3′-indane by a chiral primary amine catalyst and a protonic acid Indole]-2,2-dinitrile compounds. Background technique [0002] Chiral spiro-oxindole structural units widely exist in natural products and bioactive drug molecules. Due to the strong biological activity and high structural complexity of this type of compound-stereoselective construction of quaternary carbon centers, efficient synthesis of this type of compound is a hot spot in organic synthesis research, and has aroused great interest among organic synthetic chemists. big interest. [0003] By designing different types of reaction substrates and chiral ligands, metal-catalyzed asymmetric reactions are used to synthesize a variety of chiral spiro-oxindole, such as: asymmetric Heck reaction, asymmetric allyl substitution re...

Claims

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Application Information

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IPC IPC(8): C07D209/96C07D409/04C07D405/04C07B53/00B01J31/02
Inventor 王兴旺贾俊赵华蓝玉胞
Owner SUZHOU UNIV
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