The first cobalt-catalyzed cyanation, halogenation, and allylation via C-H activation have been realized. These formal SN-type reactions generate valuable (hetero)aryl/alkenyl nitriles, iodides, and bromides as well as allylated indoles using a bench-stable Co(III) catalyst. High regio- and mono-selectivity were achieved for these reactions. Additionally, allylation proceeded efficiently with a turnover number of 2200 at room temperature, which is unprecedented for this Co(III) catalyst. Alkenyl substrates and amides have been successfully utilized in Cp*Co(III)-catalyzed C-H activation for the first time.

CONSPECTUS. Implementation of any chemical reaction in a structurally complex setting (King, S. M., J. Org. Chem., 2014, 79, 8937) confronts structurally-defined barriers: steric environment, functional group reactivity, product instability, and through-bond electronics. But there are also practical barriers. Late stage reactions conducted on small quantities of material are run inevitably at lower than optimal concentrations. Access to late stage material limits extensive optimization. Impurities from past reactions can interfere, especially with catalytic reactions. Therefore, chemical reactions that can be relied upon at the front lines of a complex synthesis campaign emerge from the crucible of total synthesis as robust, dependable, and widely applied. Trost conceptualized ‘chemoselectivity’ as a reagent’s selective reaction of one functional group or reactive site in preference to others (Trost, B. M., Science, 1983, 219, 245). Chemoselectivity and functional group tolerance can be evaluated quickly using robustness screens (Collins, K. D., Nat. Chem., 2013, 5, 597). A reaction may also be characterized by its ‘chemofidelity’, its reliable reaction with a functional group in any molecular context. For example, ketone reduction by an electride (dissolving metal conditions) exhibits high chemofidelity, but low chemoselectivity: it usually works, but many other functional groups are reduced at similar rates. Conversely, alkene coordination chemistry effected by π Lewis acids can exhibit high chemoselectivity (Trost, B. M., Science, 1983, 219, 245), but low chemofidelity: it can be highly selective for alkenes, but sensitive to substitution patterns (Larionov, E., Chem Comm., 2014, 50, 9816). In contrast, alkenes undergo reliable, robust, and diverse hydrogen atom transfer reactions from metal hydrides to generate carbon-centered radicals. Although there are many potential applications of this chemistry, its functional group tolerance, high rates, and ease of execution have led to its rapid deployment in complex synthesis campaigns. Its success derives from high chemofidelity; its dependable reactivity in many molecular environments and with many alkene substitution patterns. Metal hydride H-atom transfer (MHAT) reactions convert diverse, simple building blocks to more stereochemically and functionally dense products (Crossley, S. W. M., Chem. Rev., 2016, 116, 8912). When hydrogen is returned to the metal, MHAT can be considered the radical equivalent of Brønsted acid catalysis—itself a broad reactivity paradigm. This Account summarizes our group’s contributions to method development, reagent discovery, and mechanistic interrogation. Our earliest contribution to this area—a stepwise hydrogenation with high chemoselectivity and high chemofidelity—has found application to many problems. More recently, we reported the first examples of a dual-catalytic cross-couplings that rely on the merger of MHAT cycles and nickel catalysis. With time, we anticipate MHAT will become a staple of chemical synthesis.

Alkene hydroarylation forms carbon-carbon bonds between two foundational building blocks of organic chemistry: olefins and aromatic rings. In the absence of electronic bias or directing groups, only the Friedel-Crafts reaction allows arenes to engage alkenes with Markovnikov selectivity to generate quaternary carbons. However, the intermediacy of carbocations precludes the use of electron-deficient arenes, including Lewis basic heterocycles. Here we report a highly Markovnikov-selective, dual-catalytic olefin hydroarylation that tolerates arenes and heteroarenes of any electronic character. Hydrogen atom transfer controls the formation of branched products and arene halogenation specifies attachment points on the aromatic ring. Mono-, di-, tri-, and tetra-substituted alkenes yield Markovnikov products including quaternary carbons within nonstrained rings.

Radical hydrofunctionalization occurs with ease using metal-hydride atom transfer (MHAT) catalysis to couple alkenes and competent radicalophilic electrophiles. Traditional two-electron electrophiles have remained unreactive. Herein we report the reductive coupling of electronically-unbiased olefins with imines and aldehydes. Iron-catalysis allows addition of alkyl-substituted olefins into imines through the intermediacy of free-radicals, whereas a combination of catalytic Co(Salt-Bu,t-Bu) and chromium salts enable a branch-selective coupling of olefins and aldehydes through the formation of a putative alkyl chromium intermediate.

Catalysis by defined transition-metal complexes has captivated the attention of the scientific community over the last decades. The well-documented utility of Rh(III) complexes in C−H activation reactions have enabled the development of a plethora of new catalytic methods. High-valent transition-metal species in C−H activation reactions were first predicted in palladium-based transformations. From those early studies, it was apparent that differences in reactivity and selectivity could be expected. By analogy, higher valent Rh(V) complexes could represent a new approach in C−H activation reactions and offer different opportunities to improve and broaden the current state-of-the-art in the field.