Entrances, Traps, and Rate-Controlling Factors for Nickel-Catalyzed C–H Functionalization

Abstract

A detailed mechanistic investigation of N-heterocyclic carbene-nickel-catalyzed hydroarylation via C−H functionalization is described. These catalysts are complicated, in part, by undesired reactivity stemming from common olefinic ligands such as cyclooctadiene (COD) that stabilize the precatalyst. This reaction adds diversity to the overall reactive landscape by permitting multiple types of ligand-to-ligand hydrogen transfer (LLHT) steps to activate the substrate arene C−H bonds. In one case, stable π-allyl complexes can be formed via LLHT to the olefin, hindering catalysis, and in the other, LLHT to the alkyne substrate leads to productive catalysis. Here, a useful map is built from extensive computational and experimental studies to guide subsequent investigations on the productive use of Ni catalysis. In addition to showing the details of catalyst deactivation, activation, and operating regimes, this article suggests the following: 1. Reductive elimination is rate-limiting and assisted by an additional alkyne ligand; 2. The resting state for catalysis is an alkyne-ligated Ni center; and 3. The reaction rate is under thermodynamic control, showing a good correlation with thermodynamics of C−H addition to the metal center (R 2 = 0.95).

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

“…[34] Such Friedel-Crafts pathways deliver branched exo-cyclization products governed by the higher stability of 28 8 carbenium ions.I nc ontrast, we observed ac omplementary endo-cyclization reactivity,w hich is in accordance with the mechanistic proposals for nickel-catalyzed hydroarylations. [35] Moreover,t his mechanism is supported by deuterium-transfer experiments.Reaction with [D] 1 -1a resulted in acomplete deuteration of the stereogenic carbon atom. No intermolecular cross-over deuteration was observed (see the Supporting Information for details).…”

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

“…The endo-cyclization selectivity is in accordance with theoretical and mechanistic studies of Ni-catalyzed hydroarylations, in which a mechanism involving direct ligand-to-ligand hydrogen transfer (LLHT) is proposed. [39] The intramolecular regio-and enantioseletive C À H cyclization of pyridines with olefins was very recently reported by Shi and co-workers (Scheme 9). [40] Among several chiral NHC ligands that were investigated, the bulky chiral saturated L11, [34] the analogue of SiPr, provided excellent catalytic activities and furnished the targeted tetrahydroquinolines and tetrahydroisoquinolines with excellent enantioinduction (up to 99 % ee).…”

“…The regioselectivity of the cyclization and results obtained from deuterium transfer experiments support a mechanism involving direct ligand-toligand hydrogen transfer. [39] In their continuing effort to develop asymmetric CÀH cyclization reactions with alkenes, Shi and co-workers recently reported the first example of catalytic enantioselective functionalization of polyfluoroarenes. [43] The reaction achieved by the use of bulky NHC ligands (L11 or L17) for Ni 0based catalysts afforded a large variety of cyclized products in high efficiency and excellent levels of chemo-, regio-, and enantioselectivity (Scheme 11).…”

“…However, while a mechanism involving CÀH oxidative addition of Ni 0 and alkene insertion is not excluded, deuterium transfer experiments indicate that direct ligand-to-ligand hydrogen transfer (LLHT) is likely the favored pathway. [39]…”

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

“…Besides 1,1-disubstitued olefins, internal 1,2-substituted olefins such as (E)-1s smoothly cyclized, delivering (+ +)-2s in good yield and enantioselectivity (entry 6). [35] Moreover,t his mechanism is supported by deuterium-transfer experiments.Reaction with [D] 1 -1a resulted in acomplete deuteration of the stereogenic carbon atom. [30] Moreover,p yrroles were found to be competent substrates,e nabling access to valuable tetrahydroindolizine scaffolds.…”