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.

Although alcohols represent one of the largest pools of commercially available alkyl substrates, approaches to di-rectly utilize them in cross-coupling and cross-electrophile coupling are limited. We report the use of alcohols in cross-electrophile coupling with aryl and vinyl halides to form C(sp3)–C(sp2) bonds in a one-pot strategy. This strategy allows the use of primary and secondary alcohols through their very fast (<1 min) in situ conversion to the corre-sponding alkyl bromides with compatible phosphonium activating reagents. The utility of the reaction is exempli-fied by its simple reaction setup, scalability, and broad scope (41 examples, 57% ± 15% ave yield). The reaction can be performed on the benchtop without the need for electro-chemical or photochemical equipment. Finally, translation to standard parallel synthesis techniques is demonstrated by successfully coupling all combinations of 8 alcohols with 12 aryl cores in a 96-well plate using only one (99% cover-age) or two (100% coverage) sets of conditions.

Although alcohols represent one of the largest pools of commercially available alkyl substrates, approaches to di-rectly utilize them in cross-coupling and cross-electrophile coupling are limited. We report the use of alcohols in cross-electrophile coupling with aryl and vinyl halides to form C(sp3)–C(sp2) bonds in a one-pot strategy. This strategy allows the use of primary and secondary alcohols through their very fast (<1 min) in situ conversion to the corre-sponding alkyl bromides with compatible phosphonium activating reagents. The utility of the reaction is exempli-fied by its simple reaction setup, scalability, and broad scope (41 examples, 57% ± 15% ave yield). The reaction can be performed on the benchtop without the need for electro-chemical or photochemical equipment. Finally, translation to standard parallel synthesis techniques is demonstrated by successfully coupling all combinations of 8 alcohols with 12 aryl cores in a 96-well plate using only one (99% cover-age) or two (100% coverage) sets of conditions.