Lewis Acid-Catalyzed Carbofluorination Reactions Via Fluoride Recycling

Abstract

Fluorinated compounds are widely employed as pharmaceuticals, agrochemicals, and polymer materials. As a result, there is a strong interest in developing more sustainable ways to make fluorinated molecules, as well as exploring their fundamental reactivity and stability. This dissertation focuses on the development of carbonyl fluorides derivatives—namely carbamoyl fluorides, acyl fluorides, and fluoroformates— as dual-function reagents that serve both as carbonyl fragments and as fluoride sources. These fluorinated building blocks were applied in the intramolecular carbofluorination of π bonds and in fluorine retentive rearrangement reactions under Lewis acid–catalyzed “fluoride shuttling” conditions. Chapter 1 provides background on fluorination chemistry, introducing common fluorinating reagents and then transitions into strategies that combine fluorine incorporation with carbon–carbon bond formation, namely the fluorinative difunctionalization of π-bonds (carbofluorination), which enables efficient construction of complex organofluorine compounds. Chapter 2 identifies a range of borane and borate-based catalysis that can activate acyl fluorides to acts as dual-function reagents. Trityl tetrafluoroborate was identified as the optimal catalyst for the synthesis of 1-(fluoromethylene)indan-2-ones from alkyne-tethered acyl fluorides, affording products with exceptional stereoselectivity under mild conditions. This method also enabled access to fluorinated scaffolds that had only been reported previously under harsher, transition metal–catalyzed conditions. Chapter 3 expands the use of Lewis acid catalyzed carbofluorination reactions to the stereoselective synthesis of 3-fluoromethylene oxindoles and γ-lactams from alkyne-tethered carbamoyl fluorides. Inexpensive, commercially available BF₃·OEt₂ identified as the optimal catalyst. Combined experimental and computational studies suggest that the reaction is initiated through oxophilic activation of the carbonyl group. This chapter also demonstrates that fluorinated secondary oxindoles can be accessed directly through a fluorocarbonylative annulation of o-alkynyl anilines. Finally, Chapter 4 details a mild and practical synthesis of fluoroformates from alcohols, employing a commercially available oxidant and a difluorocarbene source as an in situ difluorophosgene surrogate. These reaction conditions can also be applied to the synthesis of fluoro(thio)formates, carbamoyl fluorides, and acyl fluorides, providing a unified strategy for the synthesis of diverse (heteroatom)carbonyl fluoride derivatives. Preliminary studies exploring the use of fluoroformates as dual-function reagents are also presented, focusing on the fluorinative rearrangement of cyclopropylmethyl fluoroformates to fluorinated cyclobutanes.