Iridium Polypyridyl Carboxylates as Excited-State PCET Catalysts for the C(sp3)–H Abstraction and Functionalization of Amino Acid Scaffolds

Abstract

The direct C(sp3)–H arylation of amino acid scaffolds offers a concise route to stereochemically defined unnatural amino acids, but the strong, polar, and densely functionalized C–H environment of these substrates is poorly suited to conventional hydrogen atom transfer. This thesis investigates whether excited-state proton-coupled electron transfer (PCET) at an iridium polypyridyl carboxylate, in which proton and electron transfer are partitioned between a pendant carboxylate and the iridium center, can be interfaced with nickel metallaphotoredox catalysis to arylate such substrates under visible-light irradiation. A library of twelve 2,2′-bipyridine (bpy) carboxylate ligands (L1–L12) spanning electron-withdrawing to electron-donating substituents was synthesized using Negishi and P(V)-mediated cross-couplings and coordinated to an Ir(dF(CF3)ppy)2 scaffold. Giese-trapping benchmarks against strained C–H substrates (cubane, cyclobutanes and cyclopropane) identified the CF3-substituted bpy as the most capable abstractor and established a threshold abstracting strength below which the electron-rich complexes were uniformly inactive. In the dual-catalytic arylation of Boc-Pro-OMe with an electron-deficient bromopyridine, systematic screening of base, solvent, nickel ligand, and ligation protocol identified K2HPO4, acetonitrile, and pyridyl carboxamidine (PyCam) as the productive combination, delivering up to 85% analytical yield. Two variables initially masked as reproducibility issues proved mechanistically central: water content in the heterogeneous K2HPO4 base, which is required for phase-transfer deprotonation of the Ir(II)-CO2H intermediate, and the equivalence of in situ and preformed Ni(PyCam)Br2 which rules out a Cl•-mediated HAT pathway and supports PCET as the operative radical-generation step. Preliminary scope on scale-up demonstrated that the optimized conditions extend to a second amino acid substrate (Boc-Met-OMe) while exposing a scale-dependent erosion of yield. Together, these results establish iridium carboxylate PCET as a viable radical-generation modality for nickel-mediated C(sp3)–H arylation in the amino acid regime and define the operational window within which the two cycles are compatible.