Study On The Novel Synthesis Of N-Substituted Indoles Via Intramolecular Cyclization

With the increased understanding of the existed indole derivatives′application and the continuous discovery of new indole compounds in natural products, there is a demand to develop novel methods for the construction of indole compounds. This paper launches an investigation on the synthetic methodology of N-substituted indole derivatives and covers the following aspects:1. In order to construct the indole compounds by joining the N-moiety on the side chain to the benzene ring, which enables the formation of C-N bond via direct C-H functionalization, several new-type nitrenium ion intermediates were designed and synthesized: the condensation reaction betweenα-aryl-β-ketonitriles andα-aryl-β-carbonyl-carboxylates with alkylamines, arylamines, or alkoxyamines respectively were mainly studied. Furthermore, the structure and the configuration of the final products were established.2. Mediated by hypervalent organoiodine reagent, i.e. phenyliodine bis(trifluoroacetate) (PIFA), 2-aryl-3-arylamino-2-alkenenitriles and 2-aryl-3-alkylamino-2-alkenenitriles were found to undergo intramolecular cyclization to afford N-subustituted (arylated or alkylated)-indole-3-carbonitrile derivatives within a short period of time (5 mins). In addition, the benzylic cyano group in such substrates can be replaced by an ester group, which makes the method applicable to the synthesis of N-aryl or N-alkyl-indole-3-carboxylic ester derivatives. The electronic effects of the substituents on the benzene ring and the steric hindrance do not significantly alter the reaction time and yield. The reaction condition is mild and the work up procedure is simple. Owing to the fact that the nitrenium ion mechanism could not explain well some experimental result, several other mechanisms were proposed, including a nitrogen radical pathway.3. 3-Alkoxyimino-2-aryl-alkylnitriles, which could not efficiently cyclize by PIFA, could undergo intramolecular cyclization to furnish N-alkoxyindole- indole-3-carbonitrile derivatives, mediated by single electron oxidant, i.e. ferric chloride. The reaction condition is mild and the work up procedure is simple. The results of comparative experiments indicate that the benzylic cyano group in the sustrate is indispensable. Under the same reaction condition, 2-aryl-3-amino-2-alkenenitriles were unable to cyclize to give N-substituted indole derivatives. 4. In the presence of manganese dioxide, 3-alkoxyimino-2-ary-alkylnitriles can undergo intermolecular coupling to give dimer in high yields by joining the two benzylic carbons. The formed dimers substituted with methoxy group in the para or ortho positions of the benzene ring will lead to the cleavage of the formed carbon-carbon bond and the subsequent intramolecular cyclization in the presence of ferric chloride, which results in the building of N-alkoxyindole skeleton. A possible mechanism was proposed for the process. To our knowledge, the similar FeCl3-mediated carbon-carbon bond cleavage was not reported before.