Divergent construction of 3-(indol-2-yl)succinimide/maleimide and fused benzodiazepine skeletons from 2-(1H-indol-1-yl)anilines and maleimides

Abstract

In this paper, the divergent construction of 3-(indol-2-yl)succinimide/maleimide and indoyl/pyrrolyl fused benzodiazepine skeletons through the reaction of 2-(1H-indol-1-yl)anilines with maleimides is presented. Experimental mechanistic studies showed that the formation of 3-(indol-2-yl)succinimide involved Ru(II)-catalyzed and free amino group-assisted regioselective indole C2–H bond cleavage of 2-(1H-indol-1-yl)aniline followed by maleimide coordination, migratory insertion and proto-demetalation. On the other hand, the formation of the indoyl/pyrrolyl fused benzodiazepine went through an unprecedented intramolecular N-nucleophilic addition of the in situ formed 3-(indol-2-yl)succinimide followed by water elimination. In addition, 3-(indol-2-yl)maleimide could also be obtained via the dehydrogenation of 3-(indol-2-yl)succinimide. To the best of our knowledge, this is the first example in which the succinimide moiety was regioselectively introduced onto the C2-position of the indole scaffold by using a free –NH₂ unit as a directing group, which could be forged into an interesting pentacyclic scaffold in a traceless manner. In comparison, these novel methods have advantages such as easily obtainable substrates, good compatibility with sensitive functional groups, concise procedures, high regio-/chemoselectivity and excellent atom economy. Studies on the cytotoxicity of the products against several human cancer cell lines demonstrated their potential as lead compounds for the development of anticancer drugs.