CN103483344A - Method for synthesizing oxindole spiro compound - Google Patents

Abstract

The invention discloses a method for synthesizing oxindole spiro compounds, which belongs to the field of organic synthesis. A kind of ethyl (E)-2-(2-oxoindoline-3-methylene)acetate ( Ⅰ ) and ethyl 2-isothiocyanatoacetate ( Ⅱ ) catalyzed by organic base to N-substituted A method for synthesizing N-substituted 2-oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4',5'-dicarboxylic acid diethyl ester ( Ⅲ ) , the method It has the advantages of low cost, simple operation, rapid reaction and high yield.

Description

A method for synthesizing oxindole-like spiro compounds

technical field

The invention belongs to the field of organic synthesis, in particular to a method for synthesizing oxindole spiro compounds.

Background technique

Oxindole-like spiro compounds are the core structure of a class of important natural products, and have attracted much attention due to their unique biological and pharmaceutical activities. Therefore, the synthesis of oxindole-like spiro compounds has become one of the important research topics in the field of organic synthesis. The method for the synthesis of the similar oxidindole spiro compound of the present invention as reported before is as follows:

1:

Cao,Y.;Jiang,X.;Liu,L.;Shen,F.;Zhang,F.;Wang,R.Angew.Chem.,Int.Ed.2011,50,9124

2:

Tan,B.;Zeng,X.;Leong,W.W.Y.;Shi,Z.;Barbas,C.F.,III;Zhong,G.Chem.–Eur.J.2012,18,63.

The above-mentioned literatures on the synthesis of oxindole spiro compounds have used Lewis acid and substituted thiourea catalysts with complex structures, and the method provided by the present invention will use simple organic bases as catalysts.

Contents of the invention

The present invention provides (E)-2-(2-oxoindoline-3-methylene) ethyl acetate (I) and ethyl 2-isothiocyanoacetate catalyzed by N substitution with organic base (Ⅱ) Synthesis of N-substituted 2-oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4',5'-diethyl carboxylate (Ⅲ), reaction The equation is as follows:

A method for synthesizing oxindole-like spiro compounds, specifically carried out according to the following steps:

Under the protection of nitrogen, the N,N-dimethyl Add an organic base catalyst to the formamide solution and react at 25°C for 2 to 5 minutes to generate N-substituted 2-oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4' ,5'-Diethyl dicarboxylate. The ratio of ethyl (E)-2-(2-oxoindoline-3-methylene) acetate to ethyl 2-isothiocyanoacetate is 1:1.

The catalysts described therein are triethylamine, triethylenediamine (DABCO), N,N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo[5.4.0]undecyl- 7-ene (DBU), wherein DBU is the best catalyst.

The molar ratio of the catalyst is (E)-2-(2-oxoindoline-3-methylene) ethyl acetate: 0.5% to 20%.

To sum up, the present invention provides a convenient and quick method for synthesizing oxindole spiro compounds by catalyzing (I) and (II) with organic bases.

The method of the invention has the advantages of low cost, simple operation, rapid reaction and high yield.

Detailed ways

Below the present invention is given specific examples to be further described:

Example 1: Diethyl N-methyl-2-oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4',5'-dicarboxylate (Ⅲa) Synthesis:

Under nitrogen protection, (E)-2-(N-methyl-2-oxoindoline-3-methylene) ethyl acetate (Ia) (0.2g) and (II) (0.13g) DBU (0.65 mg) was slowly added dropwise to a solution of N,N-dimethylformamide (2 mL); the reaction was complete after stirring for 2 minutes. The reaction solution was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and sodium chloride solution; the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure; the crude product was purified by column chromatography to obtain N-methyl-2 -Oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4',5'-dicarboxylate (Ⅲa): 0.3g, yield: 92%, White solid mp: 231-233°C; ¹ H NMR (300MHz, CDCl ₃ ): δ (ppm) 8.15 (s, 1H), 7.38-7.32 (td, J=7.8Hz, J=1.8Hz, 1H), 7.09 -7.01(m,2H),6.91-6.88(d,J=7.8Hz,1H),5.27-5.24(d,J=8.7Hz,1H),4.39-4.23(m,3H),3.32(s,3H ),1.33(t,J=7.2Hz,3H),0.69(t,J=7.2Hz,3H). ¹³ C NMR(75MHz,CDCl ₃ ):200.0,173.5,167.6,167.4,144.5,130.0,127.4, 123.3, 123.1, 108.8, 68.3, 62.9, 61.6, 61.4, 51.8, 27.1, 14.1, 13.4.

Example 2: Diethyl N-methyl-2-oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4',5'-dicarboxylate (Ⅲa) Synthesis:

Under nitrogen protection, (E)-2-(N-methyl-2-oxoindoline-3-methylene) ethyl acetate (Ia) (0.2g) and (II) (0.13g) DBU (26 mg) was slowly added dropwise to a solution of N,N-dimethylformamide (2 mL); the reaction was complete after stirring for 2 minutes. The reaction solution was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and sodium chloride solution; the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure; the crude product was purified by column chromatography to obtain N-methyl-2 -Oxo-2'-thiospiro[indoline-3,3'-pyrrolidine]-4',5'-dicarboxylic acid diethyl ester (Ⅲa): 0.31g, yield: 95%, White solid mp: 231-233°C; ¹ H NMR (300MHz, CDCl ₃ ): δ (ppm) 8.15 (s, 1H), 7.38-7.32 (td, J=7.8Hz, J=1.8Hz, 1H), 7.09 -7.01(m,2H),6.91-6.88(d,J=7.8Hz,1H),5.27-5.24(d,J=8.7Hz,1H),4.39-4.23(m,3H),3.32(s,3H ),1.33(t,J=7.2Hz,3H),0.69(t,J=7.2Hz,3H). ¹³ C NMR(75MHz,CDCl ₃ ):200.0,173.5,167.6,167.4,144.5,130.0,127.4, 123.3, 123.1, 108.8, 68.3, 62.9, 61.6, 61.4, 51.8, 27.1, 14.1, 13.4.

The examples provided above show that the method provided by the present invention can be used to synthesize oxindole-like spiro compounds simply and efficiently, and the method has the advantages of low cost, simple operation, rapid reaction and high yield.

Claims (3)

1. a method for synthesizing oxindole class spiro compound, is characterized in that specifically carrying out according to the following steps: Under the protection of nitrogen, N-substituted (E)-2-(2-oxoindoline-3-methylene) ethyl acetate (I) and ethyl 2-isothiocyanatoacetate (II) N , Add an organic base (DBU) catalyst to the N-dimethylformamide solution, and react at 25 ^o C for 2 to 5 minutes to generate N-substituted 2-oxo-2'-thiospiro[dihydroindole-3 , 3'-pyrrolidine]-4',5'-diethyl carboxylate (Ⅲ) ; where (E)-2-(2-oxoindoline-3-methylene) ethyl acetate The molar ratio of ethyl 2-isothiocyanoacetate is 1:1. 2. a kind of method for synthesizing oxindole spiro compound according to claim 1 is characterized in that triethylamine, triethylenediamine (DABCO), N, N-diisopropylethylamine (DIPEA ) and 1,8-diazabicyclo[5.4.0]undec-7-ene as catalysts. 3. a kind of method for synthesizing oxidindole class spiro compound according to claim 1, it is characterized in that the molar ratio of catalyst is (E)-2-(2-oxoindoline-3-methylene Base) of ethyl acetate: 0.5%~20%.