Ligand‐Controlled Regiodivergent Nickel‐Catalyzed Annulation of Pyridones

Abstract

The 1,6-annulated 2-pyridone motif is found in many biologically active compounds and its close relation to the indolizidine and quinolizidine alkaloid core makes it an attractive building block. A nickel-catalyzed C-H functionalization of 2-pyridones and subsequent cyclization affords 1,6-annulated 2-pyridones by selective intramolecular olefin hydroarylation. The switch between the exo- and endo-cyclization modes is controlled by two complementary sets of ligands. Irrespective of the ring size, the regioselectivity during the cyclization is under full catalyst control. Simple cyclooctadiene promotes an exo-selective cyclization, whereas a bulky N-heterocyclic carbene ligand results in an endo-selective mode. The method was further applied in the synthesis of the lupin alkaloid cytisine.

Recent Advances in Hydrometallation of Alkenes and Alkynes via the First Row Transition Metal Catalysis

“…Following the C-H activation to form a nickel(II)-hydride species (N2), alkene insertion happened to afford nickel alkyl In 2016, Nakao and Sakaki extended the cooperative nickel/ Lewis catalysis to hydroarylation of alkenes with benzamides and aromatic ketones (Scheme 60). [170] Later, the authors described a ligand-controlled regiodivergent annulation of pyridines, selectively affording exo-or endo-cyclization products through altering the ligands (Scheme 61b). Scheme 60 Ni(0)/Lewis acid-catalyzed hydroarylation of alkenes with benzamides and aromatic ketones reported by Nakao and Sakaki In 2013, Cramer and co-workers reported an enantioselective nickel(0)-catalyzed intramolecular hydrocarbamoylation of alkenes to access optical active pyrrolidones with a chiral diaminophosphine oxide ligand (61) (Scheme 61a).…”

Chiral N‐Heterocyclic Carbene Ligands Enable Asymmetric C−H Bond Functionalization

“…In 2014, Cramer and co-workers reported a nickel-catalyzed C À H functionalization of 2-pyridones by selective intramolecular olefin hydroarylation (Scheme 7). [38] The regioselectivity of the cyclization was fully controlled by the ligand and unsymmetrical chiral NHC L16 based on the isoquinoline framework delivered selectively the endo-cyclization product with promising enantioselectivity.…”

Pyridones – Powerful Precursors for the Synthesis of Alkaloids, Their Derivatives, and Alkaloid-Inspired Compounds

“…63 Another interesting metal-activated 1,6-annulation procedure towards quinolizidines was reported by Cramer and Donets as an extension of the annulation to give indolizines shown in Scheme 19. 64 The synthesis of tetrahydroquinolizinone (Scheme 29) used Ni(cod) 2 and AlCl 3 , and also an Nheterocyclic carbene ligand (NHC ligand). These additives were recognized as responsible for the endo-cyclization mode and as the 6-membered-ring-size controller.…”