Abstract:

Development of new reactions for the introduction of C(sp3) centers is a key challenge in synthetic and medicinal chemistry. Cross-coupling (XC) and cross-electrophile coupling (XEC) reactions provide a robust platform for the introduction of these motifs. Traditional cross-coupling chemistry, for which Suzuki, Heck, and Negishi were awarded the Nobel prize in 2010 was developed using palladium catalysts. Since the initial development of these reactions, remarkable strides have been made in the palladium catalyzed coupling of C(sp2) centers. However, there is an increased interest in developing new reactions which couple C(sp3) centers. Nickel catalysts play a key role in this development because these catalysts offer unique properties suited to the challenge of activating C(sp3) coupling partners. However, while the unique reactivity of nickel catalysts in both XC and XEC reactions has been observed, the mechanistic features of these reactions remain poorly understood.

The work described herein will address both the development of new nickel-catalyzed reactions for C(sp3) coupling and the investigation of ligand-based structure reactivity relationships of nickel catalysts. Part one will introduce background on our group’s prior work developing stereospecific and stereoablative methods for the synthesis of new C–C bonds with nickel catalysis. In part two, the development of a nickel-catalyzed Kumada cross-coupling reaction will be presented. In part three, the development of a nickel-catalyzed conjunctive XEC reaction of alkyl dimesylates will be presented. 

And finally, in part four, the relationship between the one- and two-electron pathways discussed in the previously developed reactions and ligand identity will be described. An analysis of nickel-catalyzed open- and closed-shell Suzuki XC reactions in the presence of phosphine and nitrogen-based ligands will be presented.