UC Irvine

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. Nickel is more electropositive than palladium which allows it to activate weaker electrophiles. Nickel can also readily access the 0, +1, +2, and +3 oxidation states which facilitates both one- and two-electron mechanistic pathways. 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 the both the development of new nickel-catalyzed reactions for C(sp3) coupling and the investigation of ligand-based structure reactivity relationships of nickel catalysts. Chapter 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. A description will be provided for how our group has addressed synthetic challenges in constructing C(sp3)-rich frameworks by harnessing alkyl alcohol derivatives. We will also describe how through this work we uncovered aspects of nickel-catalyzed XC and XEC mechanisms. Finally we address our ongoing work evaluating the relationship between phosphine and nitrogen-based ligands and nickel-catalysts and the observed effects on reactivity in nickel-catalyzed reactions. In chapter two, the development of a nickel-catalyzed Kumada cross-coupling reaction will be presented. In this work, benzylic sulfonamides undergo cross-coupling with methyl and aryl Grignard reagents to form new C(sp3)–C(sp3) and C(sp3)–C(sp2) bonds. This work provides a method to access 1,3-acyclic fragments in high diastereomeric ratios from commercially available aryl aldehydes. We hypothesize that this reaction proceeds through a stereospecific polar oxidative addition into the C–N bond. In chapter three, the development of a nickel-catalyzed conjunctive XEC reaction of alkyl dimesylates will be presented. In this work we present a method in which alkyl mesylates tethered through an alkyl chain to an olefin, undergo a nickel-catalyzed cyclization to afford vicinal carbocycles. This method provides access to complex cyclic fragments in one synthetic step from acyclic starting materials. Mechanistic studies demonstrate that the reaction proceeds via alkyl iodides which are formed in situ from Grignard reagent. The reaction proceeds through stereoablative halogen atom abstraction to initiate cyclization. In chapter four, the relationship between the one- and two-electron pathways discussed in the previous chapters and ligand identity will be described. An analysis of nickel-catalyzed open-and closed-shell Suzuki XC reactions will be presented. We will provide data demonstrating how phosphine and nitrogen-based ligands influence the product outcomes in open- and closed-shell reactions. This demonstration of multivariable control is important for both our understanding of the mechanisms for nickel-catalyst reactions as well as the development of new methods.