High-Valent Metal and Hypervalent Iodine Mediated Fluorination

Abstract

Chapter 1 details the use of fluorine in organic chemistry and specifically its applications
in pharmaceuticals. Fluorinated compounds have broad pharmaceutical applications, where
fluorine incorporation can affect the ADME profile of drug compounds.
Introducing functional groups into an alkyl chain in a 1,3-relationship can effect
conformational control; specifically, 1,3-difluoro motifs can enable complementary control
compared to the more common 1,2-difluoro (vicinal) motifs. Both geminal and vicinal
difluorination have been achieved using alkenes as starting materials, but the analogous
1,3-difluorination remains elusive. Chapter 2 details synthetic routes towards alkyl
fluorides, including a focus on hypervalent iodine reagents and their application to alkene
fluorinations. The development of the 1,3-difluorination of homoallyl ethers using a
commercially available hypervalent iodine reagent is discussed. The transformation is
demonstrated on (hetero)aryl, benzylic, and alkyl ethers bearing a homoallyl alkene and
showing tolerance to homoallyl chain substitution. This provides a route towards the rare
1,3-difluoro moiety from readily available alkene starting materials, facilitating alkane
backbone diversification and conformational control.
The synthesis and reactivity of high-valent nickel and palladium complexes are discussed
in Chapter 3, including synthetic routes towards aryl fluorides. An in-depth study into the
current state-of-the-art in direct aryl C-H fluorination using high-valent metal fluoride
complexes is discussed, as well as attempts to translate the methodology using nucleophilic
sources of fluoride to provide a cheaper and more atom-efficient route towards reactive
reagents for fluorination. Additionally, this chapter details the design, synthesis, and
characterisation of Pd(II/IV) and Ni(II/IV) complexes and their reactivity towards direct
aryl C-H fluorination.

Date of Award	18 Jun 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Alastair J J Lennox (Supervisor) & Natalie Fey (Supervisor)