UC Irvine

Construction of new C–C bonds between two fragments in syntheses of natural products and pharmaceutically relevant compounds have been accomplished through transition metal-catalyzed cross-coupling (XC) and, more recently, cross-electrophile coupling (XEC) reactions. Specifically, nickel, a more sustainable base metal, has become more prevalent and attractive for the development of new XEC reactions due to the ability of nickel to access more oxidation states compared to palladium, allowing for the possibility of both radical and polar reactivities. Furthermore, employing alkyl pseudohalides, for example, mesylates, as coupling partners has gathered increasing interest due to the accessibility to these pseudohalides from alkyl alcohols. Herein, development and mechanistic studies of reactions involving alkyl mesylates will be discussed.A halogenation reaction of alkyl alcohols with methylmagnesium halide reagents will be discussed (Chapter 2). While Grignard reagents are commonly considered carbon-based nucleophiles, initial mechanistic studies of the nickel-catalyzed XEC reaction of 1,3-dimesylates for the synthesis of cyclopropanes determined that the Grignard reagent, methylmagnesium iodide served as not only the reductant, but also the iodide source to convert the alkyl mesylates into alkyl iodides. We saw this as an opportunity to develop a new halogenation method. Therefore, we have developed a halogenation reaction of alkyl mesylates using Grignard reagents that proceeds rapidly at low temperatures, is tolerant of various functional groups, stereospecific, and occurs with inversion, and scalable. Next, the investigation of the recombination step between the nickel and radical intermediates following halogen atom abstraction in the nickel-catalyzed XEC reaction of 1,3-dimesylates, will be discussed (Chapter 3). After iodide formation by the Grignard reagent, it was proposed that halogen atom abstraction by the nickel catalyst at the secondary center forms a secondary alkyl radical species, which recombines with the nickel(I) species to yield an organonickel(II) intermediate. The lifetime of this secondary alkyl radical intermediate was investigated through the use of radical clock experiments. Inspired by the development of the XEC reaction of 1,3-dimesylates, we looked to develop new XEC reactions involving alkyl mesylates as coupling partners. First, development of an intramolecular nickel-catalyzed XEC reaction between alkyl mesylates and allylic gem-difluorides for the synthesis of vinyl fluoride-substituted cyclopropanes was accomplished (Chapter 4). The reaction was determined to be stereospecific, and possible mechanisms were proposed based on experimental mechanistic studies and DFT calculations. Finally, an intermolecular reductive methylation reaction of alkyl mesylates with methyl tosylate was developed (Chapter 5). This reaction allows for facile conversion of secondary alkyl alcohol derivatives into secondary methyl-bearing centers. Both reactions leverage the advantages of nickel catalysis and XEC reactions and build upon mechanistic understanding of previously developed reactions.