Improved Synthesis and Reaction of 11-Chloroneocryptolepines, Strategic Scaffold for Antimalaria Agent, and Their 6-Methyl Congener from Indole-3-carboxylate

摘要

Various 11-chloro-5-methyl-5H-indolo[2,3-b]quinolines (neocryptolepines) with different substituents on the quinoline ring, key intermediates for antimalaria agents, are prepared from the substituted N-methylanilines, easily accessible by the N-methylation of anilines, and indole-3-carboxylate as a counterpart. This protocol is benign in terms of the reduced number of steps to reach the target, compared with the knownmethod using anilines, and easy product purification. Alternatively, their 6-methyl congener is prepared by N-methylation of the indole moiety of 2-arylaminoindole-3-carboxylate followed by successive cyclization and chlorination. 11-Chloroneocryptolepines are found more reactive than their 6-methyl congener in the nucleophilic substitution at the C11 position.