Nickel-Catalyzed Enantioselective Pyridone C–H Functionalizations Enabled by a BulkyN-Heterocyclic Carbene Ligand

Abstract

Annulated pyridones are an important scaffold found in many biologically active compounds. A Ni(0)-catalyzed C-H functionalization of 2- and 4-pyridones is disclosed, providing access to annulated pyridones via enantioselective intramolecular olefin hydroarylation. Key to the success of the transformation was the development of a sterically hindered and tunable N-heterocyclic carbene ligand resembling a chiral version of IPr. This ligand allows for mild reaction temperatures, and leads to the annulated pyridones in excellent yields and enantioselectivities.

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

“…[169] With a bulky NHC ligand (60), the reaction afforded para-substituted benzamides and aromatic ketones efficiently. [171] More recently, the same group disclosed an asymmetric intramolecular olefin hydroarylation of 2-and 4-pyridone, which was enabled by a sterically hindered chiral NHC ligand (62) (Scheme 61c). [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).…”

Enantioselektive C‐H‐Aktivierung mit natürlich vorkommenden 3d‐Übergangsmetallen

“…[26] In diesen Studien wurde das neuartige chirale NHC 20,b asierend auf einem vorangegangen Ligandendesign von Gawley et al [27] mit einem modifizierten Acenaphthen-Rückgrat, als universelles chirales Analogon zum bevorzugten IPr-Liganden entwickelt. [26] In diesen Studien wurde das neuartige chirale NHC 20,b asierend auf einem vorangegangen Ligandendesign von Gawley et al [27] mit einem modifizierten Acenaphthen-Rückgrat, als universelles chirales Analogon zum bevorzugten IPr-Liganden entwickelt.…”

Nickel/NHC‐Catalyzed Enantioselective Cyclization of Pyridones and Pyrimidones with Tethered Alkenes

“…As our continuing exploration in this field, we report herein a Ni/NHC‐catalyzed enantioselective C−H alkylation of pyridones and pyrimidones with alkenes, affording an array of chiral annulated products in good to excellent levels of enantioselectivity from readily available substrates (Scheme d). During the course of this research, Cramer and co‐workers reported a similar nickel‐catalyzed method for enantioselective C−H cyclization of pyridone derivatives using DM−ANIPE as a steering ligand and bulky (2,6‐ t ‐Bu 2 ‐4‐Me−C 6 H 2 O) 2 AlMe (MAD) as co‐catalyst (Scheme c) . Notably, their work represents the state‐of‐the‐art of asymmetric synthesis of chiral annulated pyridones and is the single highly enantioselective example of C−H functionalization of pyridones.…”