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

Abstract

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 Nheterocyclic carbene ligands. This protocol provides expedient access to a series of optically active 5,6,7,8tetrahydroquinolines 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.

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

“…At first, the use of the ANIPE ligand ( L1 ) and 40 mol% of AlMe 3 gave exclusively endo ‐selective C−H annulated product ( 2 a ) in quantitative yield and a promising 58% ee (Table , entry 1). This result was different from our previous report on the annulation of pyridine substrate, where MAD was exclusively effective . Further screening of ligand using an unsaturated NHC L2 gave similar enantioselectivity (entry 2), but the use of our recently developed saturated SIPE type ligands resulted in dramatical improvements in enantioselectivity ( L3 – 4 , entries 3–4).…”

A Bulky Chiral N‐Heterocyclic Carbene Nickel Catalyst Enables Enantioselective C−H Functionalizations of Indoles and Pyrroles

“…[14] Recently,e nantioselective CÀHf unctionalizations with abundant 3d-metal catalysts have gained significant momentum. [12g-h, 15, 16] In this context, asymmetric [Ni 0 ]NHC-catalyzed processes [17] -aided in several cases by Lewis acid co-activation [18] -have enabled selective C À Hfunctionalizations of pyridones, [19] pyridines, [20] and benzimidazoles. [21] However, the undirected enantioselective functionalization of the important electron-rich heterocycles pyrrole and indole remains an open challenge.…”

Mechanism and Origin of MAD‐Induced Ni/N‐Heterocyclic Carbene‐Catalyzed Regio‐ and Enantioselective C−H Cyclization of Pyridines with Alkenes

“…Recently, Shi and co‐workers reported the first example of regio‐ and enantioselective C−H activation at the C4‐position by using Ni 0 catalyst combined with bulky chiral N‐heterocyclic carbene (NHC) ligands in the presence of a sterically bulky aluminum‐based Lewis acid additive (2,6‐ t Bu 2 ‐4‐Me‐C 6 H 2 O) 2 AlMe (MAD), in cyclopentyl methyl ether (CPME). As shown in Scheme by a representative example of these reactions, with the presence of a ( R , R , R , R )‐SIPE type NHC ligand, the alkene‐tethered pyridine ( 1 ) exclusively provides the cyclization product with excellent yield (99 %) and enantioselectivity (93 % ee value, favoring R ‐configuration product in comparison with its enantiomer ), without observation of two exo ‐type cyclization products ( and ), as well as four corresponding cyclization products at the C2‐position ( , , , and ).…”