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Simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound

A technology of heterocyclic compounds and indole oxides, applied in the direction of organic chemistry, etc.

Inactive Publication Date: 2012-02-01
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As far as we know, there is no report on the synthesis of spiro[oxindole-3,5′-oxazoline] compounds by a one-step synthesis method using isatin derivatives and isocyanides as raw materials.

Method used

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  • Simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound
  • Simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound
  • Simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound

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preparation example Construction

[0018] The method for the compound shown in the preparation formula I provided by the present invention, its synthetic route is as follows:

[0019]

[0020] Among them, R 1 It can be hydrogen or C1~C6 linear or branched alkyl, C3~C8 cycloalkyl, C2~C6 alkenyl, alkynyl, aryl, aralkyl or aralkenyl;

[0021] R 2 Can be ester group, amide group, nitro group, cyano group;

[0022] R 3 It can be hydrogen, C1~C6 linear or branched alkyl, C2~C8 alkenyl, alkynyl, aryl, aralkyl, aralkenyl, acyl or alkoxycarbonyl;

[0023] R 4 It can be electron-donating or electron-withdrawing groups such as hydrogen or methyl, methoxy, halogen, nitro, trifluoromethyl, cyano, etc. at different substitution positions on the benzene ring;

[0024] In a preferred technical solution of the present invention, R 1 , R 2 , R 3 and R 4 Independently selected from one of: aryl or substituted aryl, ester or cyano, alkyl or alkoxy, substituted alkyl or halogen;

[0025] A more preferred technical solu...

Embodiment 1

[0034] Using 150mol% DABCO to catalyze the addition reaction of isatin and α-phenylisocyanoacetate to synthesize 1,2-dihydro-2-oxa-4'-phenylspiro[3H-indole-3, 5'(4'H)-oxazole]-4'-carboxylate methyl ester (in formula I, R 1 = Ph, R 2 =CO 2 Me, R 3 = H, R 4 =H) (Compound I-a).

[0035] The reaction formula is:

[0036]

[0037] Specific steps are as follows:

[0038] Isatin 48a (0.24 mmol, 35.28 mg, 1.2 equiv.), α-phenylisocyanoacetate 25 (0.20 mmol, 35 mg, 1.0 equiv.), DABCO (0.05 mmol, 5.6 mg, 0.25 equiv.) were dissolved In 1 mL of a mixed solvent of tetrahydrofuran: water = 1:2, stir at room temperature. After TLC showed that the reaction was complete, 5 ml of acetone was added to the reaction solution, and then the product was purified by flash column chromatography (petroleum ether: ethyl acetate = 1:1). 50 mg of light yellow powder was obtained with a yield of 77.9%.

[0039] 1 H NMR (CDCl 3 , TMS, 400MHz) δ7.69(bs, 1H), 7.51(s, 1H), 7.26-7.36(m, 5H), 7.20(d...

Embodiment 2

[0043] Using 150mol% DABCO to catalyze the addition reaction of 5-chloroisatin and α-phenylisocyanoacetate to synthesize 1,2-dihydro-2-oxa-4'-phenyl-5-chlorospiro[ 3H-indole-3,5'(4'H)-oxazole]-4'-carboxylic acid methyl ester (in formula I, R 1 = Ph, R 2 =CO 2 Me, R 3 = H, R 4 =5-Cl) (Compound I-b).

[0044] The reaction formula is:

[0045]

[0046] Specific steps are as follows:

[0047] Add 5-chloroisatin (0.24mmol, 43.6mg, 1.2equiv.), methyl α-phenylisocyanoacetate (0.20mmol, 35mg, 1.0equiv.), DABCO (0.3mmol, 33.6mg , 1.5equiv.) and 1ml of tetrahydrofuran: water = 1:2 mixed solvent, stirred at room temperature. Thin-layer chromatography showed that the reaction was completed after 5 hours. After adding 5 mL of acetone to the reaction tube, the product was purified by flash column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain 32.6 mg of a light yellow solid with a yield of 45.7 mg. %.

[0048] 1 H-NMR (d 6 -DMSO, TMS, 400MHz) δ10.90 (bs, 1H)...

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Abstract

The invention relates to a simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound. The spiro[oxoindole-3,5'-oxazoline] heterocyclic compound in the invention has a structural formula as represented by Fig. I. According to the invention, isatin or substituted isatin is used as a raw material, DABCO is used as alkali, and tetrahydrofuran and water (in a ratio of 1:2) are used as a mixed solvent, and the spiro[oxoindole-3,5'-oxazoline] heterocyclic compound substituted by a plurality of functional groups can be obtained in one step through Aldol condensation reaction and a cyclization reaction among the above-mentioned raw materials and isonitrile (wherein, the weight ratio of isatin to isonitrile is 1.2:1). According to the method, the reactions are simple, high yield is obtained, and a water / organics solvent is used to substitute commonly used organic solvents, being in accordance with requirements of green chemistry. Furthermore, a product of chiral spiro[oxoindole-3,5'-oxazoline] with a high d.r value and ee value can be obtained by using a chiral catalyst. The method provided in the invention enables rapid and large-scale synthesis of a library of various substituted spiro[oxoindole-3,5'-oxazoline] heterocyclic compounds to be realized and allows discovery of drug lead compounds to be accelerated.

Description

technical field [0001] The present invention relates to a novel and convenient method for synthesizing chiral and achiral spiro[oxindole-3,5'-oxazoline] heterocyclic compounds. Background technique [0002] Spiro-epoxindole compounds widely exist in many natural products and have important biological activities, so they become a special and important class of target synthetic molecules in organic synthesis. In addition, the three-dimensional shape of spiro-oxindole can be complementary to many planar heterocyclic compounds encountered in the process of new drug discovery, which has also attracted extensive attention. The challenges in the synthesis of spirocyclic skeleton compounds have always encouraged people to develop creative synthetic methods to synthesize these compounds with special and important structures. Up to now, the synthesis method of spiro-ring oxindole heterocyclic compound includes the usual cycloaddition [(a) Org. Lett.2010, 12, 1008. (b) Org. Lett.2009,...

Claims

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Application Information

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IPC IPC(8): C07D498/10
Inventor 赵梅欣唐文浩胡鹏飞李升可施敏
Owner EAST CHINA UNIV OF SCI & TECH
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