Unconventional approaches to the generation of paramagnetic species for novel synthetic methodologies

Abstract

Carboxylic acids and organotrifluoroborate salts have been extensively explored as radical precursors for organic synthesis using photocatalysis or electrochemistry. Both approaches suffer from limitations in terms of price and sustainability due to the requirement of rare metals or complex setups. My doctoral thesis aimed to expand the applicability of these bench-stable precursors by exploring alternative approaches that do not require photocatalysts or electrochemical tools. In Chapter 2, I describe the development of a method for benzylic fluorination of phenylacetic acids that was realized by forming a charge-transfer complex between the fluorinating reagent Selectfluor and the organic base DMAP. This strategy is metal-free and does not require light irradiation to form C-centered radicals. The method described is two-fold, thanks to a solvent-dependent selectivity switch that allows selectively forming the decarboxylated product in aqueous conditions, or the α-fluoro-α-arylacetic acids in anhydrous conditions. In Chapter 3, I outlined the step-by-step development of a new paradigm for light-driven cross-couplings enabled by photoactive nickel complexes that can be activated through intramolecular charge transfer (ILCT) upon blue light irradiation. I studied donor-acceptor ligands formed by installing carbazole (Cz) units and bipyridine (bpy) motifs. These ligands accessed cross-coupling reactivity without adding exogenous photocatalysts, thus bypassing the use of rare metals. The first-generation ligand design (5,5'-Czbpy) enabled C(sp2)–heteroatom using aryl iodide starting materials. By synthesizing a small library of derivatives, I identified an improved ligand design (4,4'-Czbpy) that expanded the scope to aryl bromides. Moreover, this ligand facilitated light-mediated nickel-catalyzed C(sp2)–C(sp3) cross-couplings between aryl bromides and benzyl organotrifluoroborate salts. Thanks to extensive mechanistic studies, I could provide strong evidence for a new C(sp2)–C(sp3) cross-coupling mechanism. The key finding was that this ligand enabled the unprecedented transmetalation between a nickel intermediate and the organoboron starting material. This allowed me to propose a unified mechanistic paradigm for all cross-couplings enabled by Ni(Czbpy)X2-type catalysts, featuring a light-driven activation to access the key Ni(I) intermediate, followed by “dark” nickel cycles that proceed independently of light irradiation.