Method Development and Mechanistic Investigation of Nickel-Catalyzed Reductive Coupling Processes.

Abstract

Many classes of standard organic transformations involve the coupling or cycloaddition of two different π-components to assemble a more functionalized product. Many such processes are amenable to the union of two complex fragments, thus allowing convergent approaches to complex organic molecules. A number of transition metal catalyst / reducing agent combinations are known to promote various reductive coupling processes. With respect to the nickel-catalyzed variants that are the subject of this thesis, many reducing agents have been employed, and the most widely used classes include silanes, organozincs, organoboranes, molecular hydrogen, and alcohols. The specific focus of this thesis will be the development and mechanistic investigation of nickel-catalyzed reductive processes involving the coupling of aldehyde and alkyne I-systems. Utilizing trialkylsilanes as reducing agents in nickel-catalyzed aldehyde / alkyne coupling processes allows access to various silyl-protected allylic alcohols. However, in some cases, dialkylsilane reducing agents promote a formal silylene transfer to offer direct access to oxasilacyclic products. This novel transformation was shown to be effective across a wide range of aldehyde / alkyne combinations as well as in the presence of chiral ligands to promote the first reported asymmetric transfer of a silylene synthetic equivalent. Under specific catalytic conditions, aldehyde / alkyne reductive couplings can be promoted to yield α,β-unsaturated ketones in the absence of an external reducing agent via alkyne-hydroacylation. Crossover data suggests that this coupling occurs via a previously unreported bimetallic mechanism. Intramolecular couplings proved to be facile under thermal conditions while intermolecular couplings required microwave heating. Due to the interest of nickel-catalyzed reductive coupling processes developed in our lab and others, a detailed initial-rates study of the aldehyde / alkyne / trialkylsilane variant was undertaken to better understand the role of each reactive component. Along with kinetic data, crossover and kinetic isotope effects with respect to the silane reducing agent were examined. A complete kinetic profile was obtained, and a mechanism was proposed based on the experimental findings.