Advances in Palladium-Catalyzed Allylation, Propargylation, and 1,3-Dienylation of Acetonitrile Pronucleophiles

Abstract

Presented herein is the development and application of palladium-catalyzed methods for allylation, propargylation and 1,3-dienylation of acetonitrile pronucleophiles. The developed methods focus on optimizing both atom- and step-economy during product formation thus resulting in a minimal production of waste. Further, ligand-controlled regiodivergent strategies are also presented which provide efficient access to various functionalities through a change in reaction mechanism controlled by the denticity of the coordinating ligand. In regards to the developed methods for the propargylation and 1,3-dienylation of acetonitrile pronucleophiles, the presented work provides access to these functionalities using propargylic electrophiles that were rarely observed using previously known methods. In chapter 1, a brief review of commonly employed propargylation methods is presented which often occur under harsh reaction conditions or result in a large amount of byproduct formation. Further, few exceedingly difficult palladium-catalyzed propargylation strategies are also reported that overcome the large bias for the allenyl isomer or products arising from dinucleophilic addition. Alternatively, in chapter 2, we present our ligand-controlled regiodivergent strategy for the propargylation and 1,3-dienylation of acetonitrile pronucleophiles. Specifically, we report the first palladium-catalyzed coupling of a butadiene synthon to generate 1,3-dienylated products. Further, each method provides significant advantages over commonly employed strategies to access such functionalities such as optimizing step-economy and avoiding the necessity for prefunctionalized starting materials. In chapter 3 of this dissertation, we present our ongoing efforts to expand the substrate scope of the developed regiodivergent method to nitriles possessing a pKa 17. To achieve this goal, decarboxylative cross-coupling is employed to access the reactive intermediate in situ via irreversible decarboxylation thus generating CO2 as the only byproduct. Once again, selective propargylation or 1,3-dienylation is ligand-controlled and can occur though changing the ligand from monodentate to bidentate, respectively. Lastly, in chapter 4 we present a method for the in situ activation of allylic alcohols using CO2 for the allylation of nitroalkanes, nitriles, and aldehydes. The developed method provides several advantages over commonly employed allylation strategies: (a) avoids the pre-activation of allylic electrophiles for successful cross-coupling, (b) avoids the use of additives for allylic alcohol activation, and (c) generates base in situ for pronucleophile activation thus providing an atom-economic alternative for allylic cross-coupling.