Straightforward synthesis of N-arylindoles via one-pot Fischer indolisation–indole N-arylation

Abstract

A microwave-promoted, one-pot, three-component synthesis of N-arylindoles has been developed, utilising sequential Fischer indolisation then copper(I)-catalysed indole N-arylation. Novel arylation conditions were identified that use a simple and cheap catalyst/base system (Cu₂O/K₃PO₄) in an environmentally benign solvent (ethanol), with no requirement for ligands, additives or exclusion of air or water, and microwave irradiation enabled significant acceleration of this commonly sluggish process. These conditions were designed to dovetail with Fischer indolisation, and the resulting one-pot, two-step sequence is rapid (total reaction time = 40 minutes), operationally straightforward, generally high yielding and it draws upon readily available hydrazine, ketone/aldehyde and aryl iodide building blocks. This process shows broad substrate tolerance and we have demonstrated its utility in the synthesis of 18 N-arylindoles bearing varied and useful functionality.