Atroposelective isoquinolinone synthesis through cobalt-catalysed C–H activation and annulation

Enantioselective C–H functionalization for the synthesis of chiral molecules is a challenge in organic synthesis. Although there are several methods for atroposelective C–H functionalization to form C–N axially chiral anilides based on preformed aromatic ring systems, methods that construct N-heterocycles are relatively under-explored. Here we report a cobalt-catalysed enantioselective C–H activation and annulation process for the atroposelective synthesis of isoquinolines. The reaction proceeds under mild conditions using Co(OAc)2·4H2O with a chiral salicyl-oxazoline (Salox) ligand and O2 as an oxidant. The reaction tolerates a broad range of benzamides and internal and terminal alkynes, producing a range of C–N axially chiral isoquinolinones in excellent yield and enantioselectivity (up to 98% yield and 98% e.e.). Mechanistic studies infer that the process proceeds through a CoIII/CoI catalytic cycle, with the C–N reductive elimination step being stereo-determining. The isoquinolinone products show atropostability and thermal resistance and are suitable ligands for the Pd-catalysed enantioselective C–H functionalization of indole.