Strain-Release Activation of alpha, beta-Unsaturated Amides Towards Conjugate Addition of Nitrogen, Oxygen and Sulfur Nucleophiles

This thesis encompasses a novel methodology enabling the diastereoselective addition of heteroatom-centered nucleophiles to the conjugated double bond of in situ-generated α,β – unsaturated cyclopropenyl amides. The methodology is presented as a means of activating the relatively poorly electrophilic double bond of conjugated amides via release of the ring strain which is inherent to cyclopropenes. Through strain-release activation it was demonstrated that oxygen, sulfur and nitrogen-centered nucleophilic adducts of cyclopropylcarboxamides can be efficiently synthesized. The thesis is divided into three chapters which discuss not only the development and elaboration of our chemistry, but also other methods of activating α,β – unsaturated amides and why our method will benefit the synthetic community.;Chapter one is a review of activation methods which are commonly employed to facilitate nucleophilic addition to α,β – unsaturated amides. The utility of directly functionalizing conjugated amides through nucleophilic addition is discussed, as well as why activation is necessary. The discussion is organized as a comparison of the reactivity of unactivated systems to that of activated systems; meanwhile providing an overview of what the synthetic community has done to develop this area of chemistry.;Chapter two focuses on the development of the strain-release activation method and addresses the problems and solutions associated with using inherently unstable cyclopropenes. Elaboration of the methodology to include addition of alkoxide, phenoxide and thiolate nucleophiles, both inter- and intramolecularly, to in situ generated, conjugated cyclopropenylcarboxamides is then presented and discussed. Chapter three follows up with discussion of the benefits of nitrogen-centered nucleophilic addition and the challenges we faced in accomplishing this task. Utilization of anilines, carboxamides and sulfonamides as nucleophilic amine-surrogates are presented as a viable means facilitating the addition of nitrogen-centered nucleophiles to conjugated cyclopropenes, thereby accessing biologically interesting β-aminocyclopropanecarboxylic acid derivatives.