THIOETHER LIGAND-PROMOTED CATALYTIC C–H FUNCTIONALIZATION AND MECHANISTIC INVESTIGATIONS

Abstract

While C–H functionalization is an important synthetic tool, its inherent reactivity and selectivity problems hamper its utility. In recent years, ligand-promoted catalytic C–H functionalization has demonstrated the potential to enable reduced catalyst loading, shorter reaction times, tune reaction selectivity, and increase functional group compatibility. In this thesis work, thioether ligands are introduced for Pd-catalyzed oxidative C–H functionalization of heteroarenes which improve the viability of these important reactions for applications such as the preparation of pharmaceutical intermediates and conjugated materials.

The initial discovery of simple, neutral thioethers and a second generation of anionic thioether ligands is described in Chapter 2, which promote the C–H alkenylation of furans, thiophenes, indoles, and pyrroles with high efficiency under mild conditions. These sulfur ligands accelerate reaction rate (up to ca. 800× versus control), increase the catalyst efficiency (TON up to ca. 500), and enable new site selectivity favoring hindered sites that was not previously possible using existing catalysts in the absence of directing groups.

The translation of this catalytic system to C–H arylation is discussed in Chapter 3. A practical method for the construction of oligothiophene semiconductor materials was developed, which streamlines the synthesis of a series of optoelectronic scaffolds versus classic cross-coupling approaches. Importantly, a combined experimental and computational study on this catalytic system led to the discovery of a new, distinct C–H activation mechanism termed “electrophilic concerted metalation-deprotonation” (“eCMD”). This mechanistic revision accounts for the unique thioether ligand effects that are not readily explained with existing mechanistic models for metal catalyzed C–H activation, and provides a predictive tool for selectivity control based on the structure of many metal catalysts.

A solution to the problem of catalyst poisoning by amines and Lewis basic heterocycles during C–H functionalization is described in Chapter 4, which is general to C–H alkenylation, C–H arylation, and C–H carbonylation. Applications of this approach to late-stage functionalization of drug molecules (e.g., duloxetine, clopidogrel) highlight the potential of thioether-Pd catalysts for practical C–H functionalization with functional group rich compounds commonly encountered in pharmaceutical synthesis.