Using catalyst speciation to control reactivity and address longstanding challenges in cross coupling reactions - Project Summary/Abstract The advent of cross coupling technologies has expanded access to the types of molecules available for drug screening and accelerated the synthesis of such compounds. Key to these advances in cross couplings is the discovery and application of privileged ligand scaffolds that enable high reactivity and broad substrate scope across different reaction types. In this proposal, we demonstrate that 2-phsophinoimidazole (2-PI) ligands represent a new privileged ligand class for addressing key challenges in cross coupling chemistry. Our preliminary data demonstrates that 2-PI ligands can access unique catalytic species by transforming into bidentate P–N coordination complexes, mixed N-H N-heterocyclic carbene/phosphinite complexes, or bimetallic complexes. Each of these types of catalysts achieves high reactivity in specific cross coupling reactions, and our efforts to access and favor specific catalyst structures in catalysis are providing productive solutions to difficult substrate classes in cross coupling reactions. In particular, the 2- PI ligands enable efficient catalysis in both Suzuki and Buchwald-Hartwig (BH) aminations with aryl chloride substrates, including for heterocyclic chlorides common in FDA approved pharmaceuticals. In aim 1, we will conduct structure activity studies to determine how ligand structure can influence and favor specific catalyst forms, whether it be the P–N coordination complex, N-H NHC/phosphinite formation, or bimetallic complex formation. We will then test and optimize these ligands and catalyst structures in Suzuki and BH amination reactions that employ challenging sterically hindered and heteroaryl chlorides, sensitive heteroaryl boronic acid nucleophiles, and sterically hindered amine nucleophiles. In aim 2, we will optimize catalyst structure with our 2-PI ligands to achieve efficient catalysis with a broad range of heteroaryl chloride substrates under mild reaction conditions. We will also expand our efforts to optimize Ullman-type couplings for C-O and C–S bond formation. In Aim 3, we will capitalize on the ability of our monosubstituted N-H NHC Pd complexes to perform H-bonding accelerated catalysis in Heck reactions with alkenyl alcohol substrates. We will also optimize reaction conditions for a tandem Heck/hydroalkoxylation reaction that generates tetrahydrofuran products in a single step. The studies presented herein are highly amenable to participation by undergraduate researchers and many of the optimization studies proposed will be led by senior undergraduates. The result of these studies will be new tools for synthetic and medicinal chemistry that capitalize on the potential of 2-PI ligands to transform into different metal complexes during catalysis.
