Convenient Synthesis Of 1-Aminoindole-3-carbonitriles Via FeBr₃ -Mediated Intramolecular Cyclization

N-Amino substituted indole derivatives, being an important class of compounds, have found important pharmacological properties and wide applications in chemical engineering and pharmacological areas. Therefore, more and more attention was devoted to the development of novel and general methods for the assembly of those substituted indole derivatives. Based on our previous method for the construction of indole ring system, we proposed a unique method to synthesize 1-dimethylamino indole derivatives via ferric bromide-mediated intramolecular cyclization. This method involves the aryl C-N bond formation via the direct C-H functionalization.Using different carboxylic esters and substituted arylacetonitriles as starting materials, variousα-aryl-β-ketonitriles were synthesized, followed by condensation with 1,1-dimethylhydrazine to affordα-aryl-β-hydrazono-alkylnitriles as substrates. A series of N,N-dimethylamino substituted indole derivatives were furnished via intramolecular heterocyclization ofα-aryl-β-hydrazono-alkylnitriles in the presence of ferric bromide in 1,2-dichloroethane. The reaction condition is mild, the workup procedure is simple and moderate yields were achieved. The N-moiety on the side chain was annulated to the benzene ring via direct C-H functionalization at the last synthetic step. It was also found that the cyano group at the benzylic position was indispensable and the effects of the substituents on the benzene ring were not obvious in the cyclization under the reaction condition.A series of 1-amino indole derivatives were synthesized using this method, and the structure of the compounds were characterized by 1H & 13C NMR spectra, LRMS and X-ray analysis. Mechanisms were studied for the reaction process, and one possible mechanism was proposed.