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A method for synthesizing 2-triisopropylsilylethynylindole compounds

A technology based on triisopropylsilyl and acetylene indole, which is applied in the fields of chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., which can solve the problems of difficult availability of raw materials, restrictions on application and development, and reaction The conditions are not mild, etc., and the synthesis method is simple and easy to obtain, the reaction atom is economical, and the effect of broad application prospects is achieved.

Inactive Publication Date: 2020-04-10
NANJING UNIV OF SCI & TECH
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Problems solved by technology

The raw materials for this type of reaction are not easy to obtain, some of the reaction time is very long, and the reaction conditions are not mild
For example, in 2007, the Lautens research group used 2-(2,2-dibromovinyl)aniline and trimethylsilylacetylene as reaction raw materials, palladium-carbon and cuprous iodide as catalysts, and tris(4-methoxy phenyl) phosphine as ligand, diisopropylamine as base, and toluene as solvent to generate 2-alkynylindole. Although there are many types of 2-alkynylindole generated, the reaction time is long and the reaction raw materials The synthesis is complicated (Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955-2958.)
In 2008, the Fiandanese research group selected KH as the base and N-methylpyrrolidone as the solvent at room temperature, and the yield can reach 68%. Although the reaction conditions are relatively simple, only 2-ethynylindole can be produced Restricted the further application and development of this type of reaction (Vito Fiandanese, Daniela Bottalico, Giuseppe Marchese, Angela Punzi.Tetrahedron, 20083-60.)
The reaction conditions are simple and mild, but the synthesis of hypervalent iodine reagent used in this reaction is difficult and has certain dangers, and the 2-alkynylation product of indole cannot be obtained by this method (Gergely L.Tolnai, Stephanie Ganss, Jonathan P. Brand, Jerome Waser. Org. Lett., 2013, 15, 112-115)
In 2014, Li Xingwei's research group used 1-(pyrimidinyl-2-yl)-1H-indole compounds and hypervalent iodine alkynylation reagents as substrates to (RhCp*Cl 2 ) 2 As a catalyst, zinc trifluoromethanesulfonate is used as an additive, and ethylene dichloride is used as a solvent to realize the alkynylation of the C2 position of individual indole, and a relatively ideal yield can be obtained by this method, but the applicable method Narrow range (Fang Xie, Zisong Qi, Songjie Yu, Xingwei Li.J.Am.Chem.Soc.2014,136,4780-4787)
Although the alkynylation of indole has been reported in recent years, there are still relatively few reports on the direct alkynylation of indole. Therefore, a simpler and more efficient reaction system was developed to enrich and develop the construction of 2-alkynyl indoles Compound reactions have a positive meaning

Method used

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  • A method for synthesizing 2-triisopropylsilylethynylindole compounds
  • A method for synthesizing 2-triisopropylsilylethynylindole compounds
  • A method for synthesizing 2-triisopropylsilylethynylindole compounds

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experiment example 1

[0044] Synthesis of 1-(pyrimidinyl-2-yl)-2((triisopropylsilyl)ethynyl)-1H-indole

[0045] In the reaction vessel, add indole (6mmol, 702.9mg), NaH (mass fraction 60%, 10.8mmol, 432mg), DMF solvent, react under low temperature for 30 minutes; then add 2-chloropyrimidine (9.6mmol, 1099.5mg ), the mixture was reacted at 130°C for 24 hours, after 24 hours, the reaction was monitored by TLC, diluted with ethyl acetate, transferred to a 250mL separatory funnel, washed three times with water, and after washing DMF, the organic phase was collected and washed with anhydrous sodium sulfate After removing water, the organic solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, and the compound 1-(pyrimidinyl-2-yl)-1H-indole reactant was obtained by column chromatography (ethyl acetate:petroleum ether=1:99) . Accurately weigh the 1-(pyrimidinyl-2-yl)-1H-indole reactant (0.2mmol, 39.2mg) with an electronic balance of one ten-thousandth, transfer it to...

experiment example 2

[0048] Synthesis of 4-methyl-1-(pyrimidin-2-yl)-2-((triisopropylsilyl)ethynyl)-1H-indole

[0049] Take a 100mL round bottom flask and a suitable size magnet, weigh 4-methylindole (5mmol, 656mg) and dissolve it in N,N-dimethylformamide (DMF), put it in an ice-water bath and slowly add NaH (Mass fraction 60%, 7.5mmol, 300mg) for hydrogen extraction reaction, reacted at low temperature for 1 hour, then added 2-chloropyrimidine (7.5mmol, 855mg), the mixture was reacted at 130°C for 24 hours, and passed through TLC monitored the completion of the reaction, diluted with ethyl acetate, transferred to a 250mL separatory funnel, washed three times with water, and washed DMF, collected the organic phase to remove water with anhydrous sodium sulfate, and removed the organic solvent by rotary evaporation under reduced pressure to obtain the crude product , The product 4-methyl-1H-(pyrimidin-2-yl)-1H-indole reactant was obtained by column chromatography (ethyl acetate:petroleum ether=3:95)...

experiment example 3

[0052] Synthesis of 5-methyl-1-(pyrimidin-2-yl)-2-((triisopropylsilyl)ethynyl)-1H-indole

[0053] Take a 100mL round bottom flask and a suitable size magnet, weigh 5-methyl-1H-indole (5mmol, 755mg) and dissolve it in N,N-dimethylformamide (DMF), and place it in an ice-water bath Slowly add NaH (mass fraction 60%, 7.5mmol, 300mg) for hydrogen extraction reaction, react at low temperature for 1 hour, then add 2-chloropyrimidine (7.5mmol, 855mg), and react the mixture at 130°C for 24 hours, After 24 hours, the reaction was monitored by TLC, diluted with ethyl acetate, transferred to a 250mL separatory funnel, washed three times with water, and after washing DMF, the organic phase was collected to remove water with anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure. The crude product was obtained, and the product 5-methyl-1H-(pyrimidin-2-yl)-1H-indole reactant was obtained by column chromatography (ethyl acetate:petroleum eth...

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Abstract

The invention discloses a method for synthesizing a 2-triisopropyl silicon substrate acetylene indoles compound. The method comprises the steps of firstly adopting the indoles compound as a raw material, and under an alkaline condition of sodium hydride, generating a 1-(pyrimidyl-2-base)-1H-indoles compound through the reaction of indole or substituted indole and 2-chloropyrimidine; introducing a pyridine guiding group into the indoles compound; then carrying out alkynylation reaction on the 1-(pyrimidyl-2-base)-1H-indoles compound under the participation of bispalladium dichloride, cesium carbonate, silver hexafluoroantimonate, aluminium oxide, triisopropyl silicon substrate acetylene bromine and a 1,4-dioxane solvent; finally synthesizing the 2-triisopropyl silicon substrate acetylene indoles compound. The method applies a direct C-H activation reaction method, so that a pre-functionalization process is eliminated, reaction steps are reduced, and the reaction economical efficiency is improved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis chemistry, and in particular relates to a method for synthesizing 2-triisopropylsilylindole compounds. Background technique [0002] 2-Triisopropylsilylindole homologues or derivatives are important heterocyclic compounds. The 2-triisopropylsilylindole structure exists in many active pharmaceutical molecules. It is used in materials chemistry, medicinal chemistry, dyes, etc. Wide range of applications. [0003] The method for synthesizing 2-triisopropylsilylindole compound by conventional non-C-H bond activation method can be mainly divided into two classes: [0004] One is the ring-forming reaction, generally the ring-forming reaction of 2-(2,2-dibromovinyl)aniline or 2-((trimethylsilyl)but-1,3-dien-1-yl) The ring-forming reaction of aniline is the main one. The raw materials for this type of reaction are not easy to obtain, and some reaction times are very long, and the reaction con...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/10
CPCC07F7/0812C07F7/083
Inventor 姜超赵树芳
Owner NANJING UNIV OF SCI & TECH
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