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

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

Photocatalytic Aminodecarboxylation of Carboxylic Acids

Aminodecarboxylation of unactivated alkyl carboxylic acids has been accomplished utilizing an organic photocatalyst. This operationally simple reaction utilizes readily available carboxylic acids to chemoselectively generate reactive alkyl intermediates that are not accessible via conventional two-electron pathways. The organic radical intermediates are efficiently trapped with electrophilic diazo compounds to provide aminated alkanes.Division of Chemistry. Grant Number: 146517

Activation of Alcohols with Carbon Dioxide: Intermolecular Allylation of Weakly Acidic Pronucleophiles

The direct coupling of allyl alcohols with nitroalkanes, nitriles, and aldehydes using catalytic Pd­(PPh₃)₄ has been accomplished via activation of C–OH bonds with CO₂. The <i>in situ</i> formation of carbonates from alcohols and CO₂ facilitates oxidative addition to Pd to form reactive π-allylpalladium intermediates. In addition, the formation of a strong base activates nucleophiles toward the reaction with the π-allylpalladium electrophile. Overall, this atom economical reaction provides a new C–C bond without the use of an external base and generates water as the only byproduct