Nickel-Catalyzed Functionalization Reactions Involving C–H Bond Activation via an Amidate-Promoted Strategy and Its Extension to the Activation of C–F, C–O, C–S, and C–CN Bonds

The development of functionalization reactions involving the activation of C–H bonds has evolved extensively due to the atom and step economy associated with such reactions. Among these reactions, chelation assistance has been shown to provide a powerful solution to the serious issues of reactivity and regioselectivity faced in the activation of C–H bonds. The vast majority of C–H functionalization reactions reported thus far has involved the use of precious metals. Kleiman and Dubeck reported the cyclonickelation of azobenzene and NiCp₂ in which an azo group directs a Ni center to activate the ortho C–H bond in close proximity. Although this stoichiometric reaction was discovered earlier than that for other transition-metal complexes, its development as a catalytic reaction was delayed. No general catalytic systems were available for Ni-catalyzed C–H functionalization reactions for a long time. This Account details our group’s development of Ni(0)- and Ni(II)-catalyzed chelation-assisted C–H functionalization reactions. It also highlights how the new strategy can be extended to the activation of other unreactive bonds.

In the early 2010s, we found that the Ni(0)-catalyzed reaction of aromatic amides that contain a 2-pyridinylmethylamine moiety as a directing group with alkynes results in C–H/N–H oxidative annulation to give isoquinolinones. In addition, the combination of a Ni(II) catalyst and an 8-aminoquinoline directing group was found to be a superior combination for developing a wide variety of C–H functionalization reactions with various electrophiles. The reactions were proposed to include the formation of unstable Ni(IV) and/or Ni(III) species; the generation of such high-valence Ni species was rare at that time, but since then, many papers dealing with DFT and organometallic studies have appeared in the literature in attempts to understand the mechanism. Based on our in-depth considerations of the mechanism with respect to why an N,N-bidentate directing group is required, we realized that the formation of a N–Ni bond by the oxidative addition of a N–H bond to a Ni(0) species or a ligand exchange between a N–H bond and Ni(II) species is the key step. We concluded that the precoordination of the N(sp²) atom in the directing group positions the Ni species to be in close proximity to the N–H bond which permits the formation of a N–Ni bond. Based on this working hypothesis, we carried out the reaction using KO^tBu as a base and found that the Ni(0)-catalyzed reaction of aromatic amides that do not contain such a specific directing group with alkynes results in the formation of the desired isoquinolinone, in which an amidate anion acts as the actual directing group. Remarkably, this strategy was found to be applicable to the activation of various other unreactive bonds such as C–F, C–O, C–S, and C–CN.