UCLA

This dissertation describes the development of nickel-catalyzed arylations of amides via amide C–N bond activation. Although amide C–N bonds have traditionally been considered relatively inert, recent progress in the metal-catalyzed activation of this bond has enabled cross-couplings of amide electrophiles. Herein, efforts to achieve a general nickel-catalyzed Suzuki–Miyaura cross-coupling of aliphatic amides and a strategy to improve the practicality of this parent methodology are described. Furthermore, a one-pot reductive arylation of amides wherein two different nucleophiles are added to the amide carbonyl carbon is reported. This reaction, which proceeds by way of a sequential nickel-catalyzed Suzuki–Miyaura coupling and base-catalyzed reduction cascade process, directly converts amide starting materials to chiral secondary alkyl–aryl alcohol products. Each of the methodologies presented is expected to expand the field of amide C–N bond activation methodologies and highlight the synthetic utility of amide building blocks for C–C bond-forming cross-coupling reactions. Chapter one outlines the current state of the art in nickel and iron-catalyzed cross-couplings of traditionally inert electrophiles. Specifically, recent advances in base-metal-catalyzed reactions of phenol, aniline, ester, and amide derivatives that proceed via aryl or acyl C–O/C–N bond activation are described. This brief review should provide context for the subsequent studies presented in this dissertation. Furthermore, summarizing recent efforts in this field is expected to highlight the utility of base-metal-catalyzed cross-couplings of traditionally-inert electrophiles in organic synthesis. Chapters two and three describe the development of nickel-catalyzed Suzuki–Miyaura cross-couplings of aliphatic amide derivatives. Chapter two details a general nickel-catalyzed arylation of aliphatic amides, where mild cleavage of the aliphatic amide C–N bond is made possible using a nickel(0)–N-heterocyclic carbene (NHC) catalyst–ligand system. The methodology specifically focuses on the union of heterocyclic fragments to assemble poly-heterocyclic ketone scaffolds. In addition, a stereoretentive Suzuki–Miyaura coupling is described, wherein amides bearing epimerizable -stereocenters undergo the reaction with minimal erosion of stereochemistry. Chapter three outlines a strategy for performing nickel-catalyzed Suzuki–Miyaura couplings of aliphatic amides on the benchtop. In this approach, air- and moisture-sensitive reagents are stored in paraffin capsules, allowing for air-sensitive transition-metal-catalyzed cross-couplings to be carried out without the need for glovebox manipulations. Both studies are anticipated to advance the utility of amides as acyl synthons for C–C bond-forming cross-coupling reactions. Chapters four and five concern the development of a base-catalyzed reduction of aryl ketones and its application toward a one-pot reductive arylation of aliphatic amides. In chapter four, the use of an electron-rich benzylic alcohol reductant to achieve a Meerwein–Ponndorf–Verley (MPV)-type reduction of ketones is reported. This approach avoids the use of the hydride source as the solvent, proceeds under mildly basic conditions, reduces aromatic and �O- and S-containing heteroaromatic ketones, and delivers enantioenriched alcohol products through a stereospecific reduction when using an enantioenriched reductant. These studies expand the field of base-catalyzed MPV-type reductions of carbonyls and address several limitations associated with prior methodologies. Chapter five describes the the application of this mild ketone reduction protocol toward a one-pot reductive arylation of amides. Specifically, this methodology, which proceeds by way of a nickel-catalyzed Suzuki–Miyaura coupling of aliphatic amides and subsequent base-catalyzed transfer hydrogenation of ketone intermediates, provides direct access to chiral secondary alkyl–aryl alcohols from amide starting materials. This study represents the first catalytic method for the direct intermolecular addition of two different nucleophiles to the amide carbonyl carbon. Moreover, these efforts are expected to promote the development of additional catalytic approaches to directly convert carboxylic acids and their derivatives to functional groups bearing stereogenic centers.