Indium-Catalyzed Annulation of o-Acylanilines with Alkoxyheteroarenes: Synthesis of Heteroaryl[b]quinolines and Subsequent Transformation to Cryptolepine Derivatives

Abstract

We disclose herein the first synthetic method that is capable of offering heteroaryl[<i>b</i>]quinolines (HA[<i>b</i>]Qs) with structural diversity, which include tricyclic and tetracyclic structures with (benzo)thienyl, (benzo)furanyl, and indolyl rings. The target HA[<i>b</i>]Q is addressed by the annulation of <i>o</i>-acylanilines and MeO-heteroarenes with the aid of an indium Lewis acid that effectively works to make two different types of the N-C and C-C bonds in one batch. A series of indolo[3,2-<i>b</i>]quinolines prepared here can be subsequently transformed to structurally unprecedented cryptolepine derivatives. Mechanistic studies showed that the N-C bond formation is followed by the C-C bond formation. The indium-catalyzed annulation reaction thus starts with the nucleophilic attack of the NH₂ group of <i>o</i>-acylanilines to the MeO-connected carbon atom of the heteroaryl ring in an S_NAr fashion, and thereby the N-C bond is formed. The resulting intermediate then cyclizes to make the C-C bond through the nucleophilic attack of the heteroaryl-ring-based carbon atom to the carbonyl carbon atom, providing the HA[<i>b</i>]Q after aromatizing dehydration.