Although alcohols are one of the largest pools of alkyl substrates, approaches to utilize them in cross-coupling and crosselectrophile coupling are limited. We report the use of 1°and 2°alcohols in cross-electrophile coupling with aryl and vinyl halides to form C(sp 3 )− C(sp 2 ) bonds in a one-pot strategy utilizing a very fast (<1 min) bromination. The reaction's simple benchtop setup and broad scope (42 examples, 56% ± 15% average yield) facilitates use at all scales. The potential in parallel synthesis applications was demonstrated by successfully coupling all combinations of 8 alcohols with 12 aryl cores in a 96-well plate.

The mechanism of catalytic allylic C-H amination reactions promoted by Cp*Rh complexes is reported. Reaction kinetics experiments, stoichiometric studies, and DFT calculations demonstrate that allylic C-H activation to generate a Cp*Rh(π-allyl) complex is viable under mild reaction conditions. The role of external oxidant in the catalytic cycle is elucidated. Quantum mechanical calculations, stoichiometric reactions, and cyclic voltammetry experiments support an oxidatively induced reductive elimination process of the allyl fragment with an acetate ligand. Lastly, evidences supporting the amination of an allylic acetate intermediate is presented. Both nucleophilic substitution catalyzed by Ag + that behaves as a Lewis acid catalyst and an inner-sphere amination catalyzed by Cp*Rh are shown to be viable for the last step of the allylic amination reaction.

Strained rings are increasingly important for the design of pharmaceutical candidates, but crosscoupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all-carbon quaternary centers is the coupling of abundant strained-ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel-catalyzed cross-electrophile approach that couples a variety of strained ring N-hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t-Bu BpyCam CN , an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96-well plates.

Strained rings are increasingly important for the design of pharmaceutical candidates, but cross‐coupling of strained rings remains challenging. An attractive, but underdeveloped, approach to diverse functionalized carbocyclic and heterocyclic frameworks containing all‐carbon quaternary centers is the coupling of abundant strained‐ring carboxylic acids with abundant aryl halides. Herein we disclose the development of a nickel‐catalyzed cross‐electrophile approach that couples a variety of strained ring N‐hydroxyphthalimide (NHP) esters, derived from the carboxylic acid in one step, with various aryl and heteroaryl halides under reductive conditions. The chemistry is enabled by the discovery of methods to control NHP ester reactivity, by tuning the solvent or using modified NHP esters, and the discovery that t‐BuBpyCamCN, an L2X ligand, avoids problematic side reactions. This method can be run in flow and in 96‐well plates.

Strained rings are increasingly important for the design of pharmaceutical candidates due to their improved pharmacokinetic and safety profiles, as well as their ability to orient substituents into favorable geometries for the potential improvement of the binding affinity to the biological target. Despite their importance, methodologies to cross-couple strained rings have been underdeveloped. The most abundant source of strained carbocycles and heterocycles is the corresponding carboxylic acid, making methods that employ this substrate pool attractive. Coupling of these carboxylic acids with halides, a second source of abundant building blocks, would allow for rapid access to a diverse set of functionalized carbocyclic and heterocyclic frameworks containing all-carbon quaternary centers. Herein we disclose the development of a nickel-catalyzed cross-electrophile approach that couples a variety of strained ring N-hydroxyphthalimide esters, derived from the carboxylic acid in one step or in situ, with various aryl and heteroaryl halides under reductive conditions. The key to this success was the electronic modification of the NHP ester to make them less reactive, as well as the discovery of a new ligand, t-BuBpyCamCN, that avoids problematic side reactions. This method enables the incorporation of 3-membered rings, 4-membered rings, and bicyclic fragments onto (hetero)arenes derived from (hetero)aryl iodides and (hetero)aryl bromides, allowing for straightforward and direct access to arylated strained rings.