Computational approaches to explore mechanisms of Pd/1,4-azaborine-biarylphosphine catalyzed hydrofunctionalization of 1,3-enynes

Overview & Synopsis

This dissertation concerns the chemistry of 1,4-azaborines, resulting from the replacement of two carbon atoms in benzene/naphthalene by a boron and a nitrogen atom at the 1- and 4-positions. In general, the introduction of boron-nitrogen atoms into aromatic systems creates new chemical space which can be exploited in a variety of fields, including materials, energy storage, medicinal chemistry, and homogeneous catalysis. We aimed to leverage 1,4-azaborines’ potential as supporting ligands in transition metal catalysis through a combination of experimental and computational chemistry.Using computational chemistry, we helped develop efficient and selective new catalytic methods enabled by phosphino-1,4-azaborine ligands. In particular, we investigated the detailed mechanisms of the palladium-catalyzed additions of C−H, S−H, and O−H bonds regioselectively to 1,3-enynes.We first investigated the hydroalkylation of 1,3-enynes with ketones to generate allenes, enabled by cooperative Pd-azaborine/B(C6F5)3/amine catalysis. Allenes are common structural motifs in natural products, bioactive molecules and versatile synthetic intermediates. Through synergistic mechanistic studies involving Density Functional Theory (DFT) calculations and experiments, an outer-sphere protonation pathway involving a nucleophilic addition to form the C−C bond was proposed with a Pd-π-allyl B(C6F5)3 adduct as off-cycle resting state. Using Activation Strain Model (ASM), a powerful and robust method for analyzing and understanding chemical processes, we concluded that steric hindrance introduced by the catalyst plays a pivotal role in the regioselectivity of the reaction. This result prompted us to design a new ligand which could favor the formation of 1,3-dienes, important building blocks in Diels-Alder reactions and in polymerization processes.We also investigated the Pd-azaborine/B(C6F5)3-catalyzed trans-hydrothiolation of internal 1,3-enynes. Detailed exploration of the plausible pathways allowed us to identify the key role of B(C6F5)3 in promoting the outer-sphere protonation pathway which is responsible for the regioselectivity of the reaction. Without B(C6F5)3, a classical inner-sphere pathway is preferred, leading to cis-addition products.Finally, we conducted mechanistic studies of a Pd-azaborine/B(C6F5)3-catalyzed endo-selective intramolecular hydroalkoxylation of 1,3-enynes. This reaction affords medium-sized oxygen-containing heterocycles, which are common structures in natural products and important in medicinal chemistry. An outer-sphere pathway involving protonation of a Pd(0)-bound enyne followed by nucleophilic attack on the resulting Pd-π -allyl intermediate has been predicted as the operative mechanism.In summary, this thesis provides an in-depth study of novel, highly selective hydroalkylation, hydrothiolation and hydroalkoxylation reactions, enabled by Pd-azaborine/B(C6F5)3 cooperative catalysis. Each of these reactions occurs via an outer sphere-mechanism but with a different preferred pathway, highlighting the importance of the joint computational chemistry/experimental approach to better understand and describe metal-catalyzed reactions. These studies also revealed the revealed the higher efficiency of phosphino-1,4-azaborine ligands vs their all-carbon analogues in Pd-catalyzed hydrofunctionalization reactions, highlighting their potential for the development of more selective and efficient synthetic methodologies.