Expanding the Scope of Nickel-Catalyzed C(sp2)–N/O Cross-Coupling Reactions Using Tailored Ancillary Ligands

Abstract

The ubiquity of aryl C–N/O bonds in pharmaceuticals and natural products necessitates the development of robust and selective methodologies to construct such linkages efficiently. Palladium-catalyzed C(sp2)–N/O cross-coupling has become a widely utilized method for the synthesis of aryl C–N/O bonds, however, the high cost and scarcity of palladium has spurred researchers to examine the use of inexpensive, Earth-abundant metals in these reactions. Though nickel has emerged as a suitable alternative to palladium in C(sp2)–N cross-coupling, many nickel catalyst systems ‘repurpose’ ancillary ligands that demonstrated prior utility with palladium with limited success. Recently, the use of a tailored ancillary ligand, PAd-DalPhos, in nickel-catalyzed monoarylations of ammonia and primary alkylamines enabled an unprecedented scope of electrophiles to be cross-coupled at room temperature, demonstrating the power of applying tailored ancillary ligands in challenging nickel-catalyzed cross-coupling reactions. Inspired by the success of the PAd-DalPhos ligand system, this thesis focused on the development of new nickel-catalyzed C(sp2)–N/O cross-coupling reactions mediated by tailored ancillary ligands, with the goal of improving upon state-of-the-art metal-catalyzed procedures, or establishing reactivity with nickel that had not been observed previously. Chapter 2 details the nickel-catalyzed N-arylation of cyclopropylamine using 2-C3, a pre-catalyst containing the tailored ancillary ligand CyPAd-DalPhos (2-L3). Using this pre-catalyst, the desired transformation was achieved for the first time, largely under mild conditions (3 mol % Ni, 25 ºC), tolerating a variety of (hetero)aryl (pseudo)halide electrophiles. In Chapter 3, the first nickel-catalyzed C(sp2)–O cross-coupling without recourse to photoredox catalysis is disclosed, where pre-catalysts 2-C3 and 2-C1, containing 2-L3 and PAd-DalPhos (2-L1) respectively, facilitate the reaction of primary, secondary, and tertiary aliphatic alcohols with various (hetero)aryl electrophiles, including unprecedented reactivity with chlorides and pseudohalides. Finally, the nickel-catalyzed C(sp2)–N cross-coupling of bulky, primary alkylamines with (hetero)aryl halides using pre-catalyst 4-C1, incorporating PhPAd-DalPhos (4-L1), is discussed in Chapter 4, expanding the scope of this transformation with nickel, and establishing room temperature reactivity for the first time with this class of nucleophile in metal-catalyzed cross-couplings.