UC Irvine

Cross-coupling (XC) reactions have had a lasting impact on the way synthetic organic chemists approach bond construction. This is evident by the numerous industrial applications of XC methods and the 2010 Nobel prize awarded to Ei-ichi Negishi, Akira Suzuki, and Richard Heck. Palladium-catalyzed XC reactions have dominated the field and are now very well understood transformations. However, development of cross-electrophile coupling (XEC) reactions has moved slower than that of traditional XC reactions. XEC reactions offer attractive counterparts to traditional XC reactions as XEC reactions couple two electrophilic partners together, utilizing a widely accessible pool of halide and pseudohalide starting materials. Additionally, these transformations are commonly achieved using nickel catalysis, which offers practical advantages over the commonly used palladium catalysts. For example, nickel has a smaller carbon footprint associated with the mining of the metal making it a more sustainable alternative to precious metals such as palladium. Thus, the advancement of nickel-catalyzed XEC reactions will allow for the development of transformations that utilize readily accessible functional group motifs with sustainable base metal catalysis. Cyclopropane motifs are a common functional group found in pharmaceutical compounds and natural products. There are a variety of methods that synthesize cyclopropane motifs from either alkenes or diazo compounds including the Simmons–Smith reaction. However, there are few cyclopropanation methods that utilize simple C–O and C–N bonds as precursors. We foresaw nickel-catalyzed XEC reactions as a unique way to approach cyclopropane synthesis. Herein, a nickel-catalyzed XEC reaction of 1,3-dimesylates to access aryl- and alkylcyclopropanes is described. Additionally, by developing a mild set of reaction conditions, we foresaw the opportunity to develop a late-stage modification of medicinal agents such as statins. A zinc-mediated XEC reaction of 1,3-dimesylates for cyclopropane synthesis has also been described. Finally, domino reactions have become an attractive way to quickly build molecular complexity by undergoing multiple synthetic manipulations in a single step. Specifically, our lab foresaw the opportunity to build upon our previously developed nickel-catalyzed ring contraction of sulfonamides. Therefore, we have developed a domino XEC dicarbofuntionalization reaction of propargyl N-tosyl sulfonamides for cyclopropane synthesis. The rapid development of palladium-catalyzed XC methods was aided by mechanistic understanding of the various transformations. While mechanistic investigation of nickel-catalyzed XEC reactions has been performed, there are still key features involved in nickel catalysis that have yet to be addressed including the control of reactivity that the ligand imparts on the nickel catalyst. We foresaw the 4-halotetrahydropyrans (THP) as interesting model substrates for the study of ligand-based control of nickel-catalysts. Phosphine ligands were predicted to selectively engage the carbon–oxygen bond via a two-electron oxidative addition pathway to access a cyclopropane product. Conversely, nitrogen-based ligands were predicted to selectively engage the carbon–halogen bond in a one-electron oxidative addition pathway resulting in the reduced tetrahydropyran. Herein, a series of vinyl, naphthyl, and biphenyl THPs were examined with a series of phosphorous- and nitrogen-based ligands where two factors work in concert to determine chemoselectivity: the degree of C–O bond activation and the type of ligand employed.