Coupling Catalytic Alkene Hydroacylation and α‑Arylation: Enantioselective Synthesis of Heterocyclic Ketones with α‑Chiral Quaternary Stereocenters

We report a strategy that combines alkene hydroacylation and enantioselective α-(hetero)­arylation reactions to form a wide variety of nitrogen-containing heterocyclic ketones bearing α-chiral quaternary stereogenic centers. Exo-selective, intramolecular Ni-catalyzed hydroacylations of <i>N</i>-homoallylindole- and <i>N</i>-homoallylpyrrole-2-carboxaldehydes form α-substituted six-membered heterocyclic ketones in up to 95% yield, while N-heterocyclic carbene (NHC) catalyzed hydroacylations of <i>N</i>-allylindole- and <i>N</i>-allylpyrrole-2-carboxaldehydes form α-substituted five-membered heterocyclic ketones in up to 99% yield. The racemic five- and six-membered products of Ni- and NHC-catalyzed hydroacylation reactions are readily transformed into heterocyclic ketones containing an α-chiral quaternary stereogenic center by enantioselective Ni-catalyzed α-arylation and α-heteroarylation reactions. The chiral, nonracemic products formed through a combination of alkene hydroacylation and α-(hetero)­arylation reactions are formed in moderate to high yields (44–99%) with excellent enantioselectivities (typically >95% ee). The identity of the precatalyst for Ni-catalyzed α-(hetero)­arylation is dictated by the identity of the α-substituted heterocyclic ketone starting material. α-(Hetero)­arylations of six-membered heterocyclic ketones occur at 65–85 °C in the presence of a catalyst generated in situ from Ni­(COD)₂ and (<i>R</i>)-BINAP or (<i>R</i>)-DIFLUORPHOS. α-(Hetero)­arylation of five-membered heterocyclic ketones must be conducted at room temperature in the presence of an [((<i>R</i>)-BINAP)­Ni­(η²-NC-Ph)] precatalyst or a catalyst generated in situ from Ni­(COD)₂, (<i>R</i>)-DIFLUORPHOS, and benzonitrile.