Enantio- and Regioselective Ni-Catalyzed para-C-H Alkylation of Pyridines with Styrenes via Intermolecular Hydroarylation.

Direct asymmetric functionalization of the pyridyl C-H bond represents a longstanding challenge in organic chemistry. We herein describe the first enantioselective para-C-H activation of pyridines through the use of a Ni-Al bimetallic catalyst system and N-heterocyclic carbene (NHC) ligand for intermolecular hydroarylation of styrenes. The reaction procceds in high to excellent enantioselectivities (up to 98.5:1.5 er) and high site-selectivities for both styrene and pyridine components (up to >98:2). Consequently, a broad range of enantioenriched 1,1-diarylalkanes containing pyridine moieties could be prepared in a single step with 100% atom economy. Computational studies supported a mechanism involving a ligand-to-ligand H-transfer (LLHT) and reductive elimination sequence, with LLHT being the rate- and enantioselectivity-determining step. DFT studies indicate that the π-π stacking interaction between the NHC aryl fragment and trans-styrenes is critical for high reactivity and enantiocontrol.

Regio- and Enantioselective C-H Cyclization of Pyridines with Alkenes Enabled by a Nickel/N-Heterocyclic Carbene Catalysis.

Annulated pyridines are ubiquitous scaffolds in many bioactive molecules. A highly regio- and enantioselective Ni(0)-catalyzed endo-selective C-H cyclization of pyridines with alkenes has been developed. An unprecedented enantioselective C-H activation at pyridyl 3- or 4-positions was enabled by bulky chiral N-heterocyclic carbene ligands. This protocol provides expedient access to a series of optically active 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydroisoquinolines, compounds otherwise accessed with difficulty, in moderate to high yields (up to 99% yield) and enantioselectivities (up to 99% ee). To our knowledge, this is the first example of enantioselective C-H cyclization of pyridines to chiral annulated products.