Study On The Novel Synthesis Of 2-Amido-indoles Via Ynamides

With the increased understanding of the existed 2-amido-indole derivatives'application and the continous discovery of new 2-amido-indole compounds in natural products, there is a demand to develop novel methods for the construction of 2-amido-indole compounds. This thesis launched an investigation on the synthetic methodology of N-substituted-2-amido-indole derivatives and covered the following aspects:According to the process already reported, various substituted 2-haloaromatic aldehydes were prepared. Then the 2-haloaromatic aldehydes were used to prepare 1-(2,2-dibromovinyl)-2-haloaromatic compounds via Corey-Fuchs reaction. The results of comparative experiments indicated that types and positions of substituents on the aromatic ring did not significantly affect the reaction. 2-Haloaryl acetylenic bromides were directly obtained from 1-(2,2-dibromo vinyl)-2-haloaromatic compounds through elimination reaction, for which the benzyltriethyl ammonium bromide catalyst combined with 60% potassium hydroxide solution in dichloromethane proved to be efficient. The effects of substituents on the aromatic ring were investigated, and thirteen new 2-Haloaryl acetylenic bromides with various substituents were synthesized.This paper focused on the selective amidative cross-coupling of sp-hybridized carbon-bromine bond and sp2-hybridized carbon-halogen bond with amides catalyzed by transition metal. By employing 10 mol % of CuSO4.5H2O and 20 mol % of 1,10-phenanthroline combined with K2CO3 in toluene proved to be efficient for highly selective Csp-N formation which led to ortho-haloaryl substituted ynamides. The effects of substituents of substrates and amides were studied, which showed that the types of amides had much effect on the reaction, while the substituents on aromatic ring had only a little effect. Twenty five new ortho-haloaryl substituted ynamides were synthesized and characterized by NMR spectra, MS and IR.The application of ortho-haloaryl substituted ynamides was investigated in the synthesis of 2-amido-indoles, which involved a tandem manner of ortho-haloaryl substituted ynamides with amines catalyzed by transition metal. A series of ortho-haloaryl substituted ynamides were converted to corresponding N-substituted-2-amido-indole derivatives with diverse substituted amines via palladium-catalyzed tandem reaction under the catalyst of Pd2(dba)3, the ligand of Xphos and the base of Cs2CO3 in toluene or dioxane. This paper investigated the effects of substituents and amines, and proposed a possible mechanism which involved Buchwald-Hartwig cross coupling reaction and 5-endo-dig cyclization reaction. Seventeen new N-substituted-2-amido- indole derivatives were synthesized and characterized by NMR spectra, MS and IR. The compound IN7 was also identified by X-ray crystallography. The reaction condition was mild and the work up procedure was simple.