Indole Synthesis from an Alkynyl-Containing Conjugated System: Substrate Scope and Application in Total Synthesis

An efficient synthetic method to rapidly assemble the indole scaffold from an ortho-aminobenzyl-substituted alkynyl-containing conjugated system was reported. This one-pot procedure involves an intramolecular aza-Michael addition followed by spontaneous alkene isomerization, affording the annulation product structurally characterized with an electron-withdrawing group on the C2 side chain. The developed methodology is conducted under mild reaction conditions and has broad substrate scope, wherein conjugated aldehyde, ketone, ester, amide, phosphonate, and sulfone are all amenable substrates. Furthermore, the formal intermolecular (4 + 1) annulation of ortho-aminobenzyl bromide and an alkynyl-containing conjugated system was also realized to directly introduce the indole backbone in a synthetically practical manner. Lastly, to demonstrate the synthetic utility, efficient total syntheses of 4,4'-dimethylindigo and quindoline were achieved in 6 and 5 steps, respectively.