Ligand (biochemistry)

Yield (engineering)

Receptor

Organic chemistry

Combinatorial chemistry

Stereochemistry

Enantioselective synthesis

Catalysis

Oxazoline

Chemistry

Metallurgy

Materials science

Annulation

Biochemistry

Nature Synthesis

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.                                                                                                        Atroposelective synthesis of C–N axially chiral anilides typically requires preformed aromatic ring systems. Now, a cobalt-catalysed atroposelective C–H activation and annulation method to construct isoquinolinones from benzamides, with C–N axially chirality, is reported. Using a chiral salicyl-oxazoline ligand and O2 as an oxidant, the method yields isoquinolines in excellent yields and enantioselectivities.

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