New Platforms for Incorporation of Fluorine-Containing Motifs

Fluorine’s profound influence on the physicochemical and physiological attributes of compounds has led to their widespread use in materials, agrochemicals, and pharmaceuticals. Despite their importance, synthesizing fluorinated compounds presents challenges due to costly fluorine sources, limited functional tolerance, and inefficiencies in step economy. Addressing these issues, we sought to streamline and enhance fluorinated compound synthesis using contemporary methodologies.

Aligned with the Martin group’s expertise in activating inert bonds and Ni-catalyzed reactions, my doctoral research has concentrated on innovating approaches for integrating gem-difluoroalkenes, monofluoroalkanes, and gem-difluoroalkanes. Those approaches have involved concepts such as C-H functionalization (chapter 2, 3), chain-walking (chapter 3), hydrofunctionalization (chapter 3, 4), halogen-atom-transfer (XAT) (chapter 4), and super-electron-donors (SEDs) (chapter 5).

The initial research section centers on advancing a switchable catalytic defluorinative sp³ C-H alkylation of secondary amides (chapter 2). This method rapidly and reliably integrates gem-difluoroalkene motifs into previously untouched sp³ positions. Control and modulation of site selectivity are effortlessly achieved through judicious catalyst and amide backbone choices.

The subsequent research section involves crafting a catalytic monofluoroalkylation strategy for both terminal and internal olefins via “Ni-H” chemistry (chapter 3).

Then, we extend our investigations into the difluoroalkylation of olefins (chapter 4). A harmonious interplay of halogen- and hydrogen-atom transfer underpins our method, ushering in a fresh pathway for crafting sought-after difluorinated alkyl bioisosteres with implications for drug discovery.

To further simplify the integration of gem-difluoroalkanes, a de novo α-difluoroalkylation of benzyl amines utilizing trifluoromethylarenes has been accomplished (chapter 5), which holds the potential to streamline the synthesis of medicinally-relevant α-difluoroalkylated amines from basic precursors.

In summary, we present innovative and effective strategies for synthesizing gem-difluoroalkenes, monofluoroalkanes, and gem-difluoroalkanes. These transformations, notable for their wide applicability, gentle reaction conditions, and precise site-specificity, introduce a complementary paradigm to craft intricately functionalized and medicinally-relevant fluorinated compounds from readily available, uncomplicated starting materials.

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