title: Applications of main-group reagents in C-S, C-F and C-N bond forming reactions
Creators: name: Cironis, Nojus
Publisher: name: The University of Edinburgh
Year: 2025
Subjects: subject: Main-group reagents
subject: Sulfenylation
subject: Nucleophilic fluorination
subject: Transborylation
subject: Heterocycles

description: For decades, main-group reagents have been applied to a range of organic transformations, some of which have been Noble prize winning – e.g. Suzuki-Miyaura cross-coupling or hydroboration, to name a few. Boron- and sulfur-containing reagents have been established as particularly valuable in synthetic chemistry, facilitating the formation of various C-X bonds (where X = S, F, N, B, etc.). However, some of these transformations utilise rare transition-metal catalysts and/or harsh reaction conditions which might pose difficulties in industrial applications (e.g. the necessity towards removal of traces toxic metals from active pharmaceutical ingredients). The results presented in this thesis seek to address some of these limitations and expand the synthetic toolbox of sulfenylation, nucleophilic fluorination and N-heterocycle-forming reactions by utilising main-group boron- and sulfur-based reagents. Chapter 1 of this thesis discusses the use of commercial XtalFluor salts (e.g. XtalFluor-E and XtalFluor-M) in sulfenylation reactions of arene nucleophiles through SEAr. To date, XtalFluor reagents have primarily been used with oxygen-based nucleophiles (e.g. alcohols, carbonyls), particularly in deoxyfluorination reactions. This chapter expands the utility of XtalFluor salts towards the regioselective C3-H sulfenylation reaction of indoles for the synthesis of di-indole-sulfides. The addition of exogenous amine bases significantly impacted the reaction outcome by forming Lewis adducts with XtalFluor-E. This chapter marks the first synthetic protocol where XtalFluor-E was directly used in electrophilic aromatic substitution to form C-S bonds. Chapter 2 of this thesis explores the development of a straightforward synthetic route towards F-9-B-BBN and its applications in nucleophilic fluorination reactions, such as fluoroboration (i.e. akin to hydroboration) and deoxyfluorination. The developed synthetic route towards F-9-B-BBN represents a significant improvement over previous approaches in the fluoroborane synthesis that primarily used toxic and difficult-to-handle fluoride sources (e.g. SbF3). The utility of F-9-B-BBN was then tested in the fluoroboration reaction of α,β-unsaturated Michael acceptors with tethered Lewis basic functionalities (e.g. Weinreb amides, pyridine-2-thiol esters). Ultimately, the activation of the B-F bond towards nucleophilic fluoride transfer/fluoroboration was unsuccessful due to the formation of unreactive adducts between the Lewis basic sites (e.g. carbonyl or amide) and F-9-B-BBN. However, activation of the B-F bond was achieved in deoxyfluorination reactions of O-alkylisoureas, which resulted in the formation of alkyl-fluorides. Importantly, a unique side-reaction was observed between F-9-B-BBN and isoureas, resulting in the formation of DCC and alkoxy-9-B-BBN. Chapter 2 underlines the importance of this side-reaction by exploiting it to develop highly selective deoxyfluorination protocol of poly-isourea substrates, which showed unprecedented selectivity for secondary position over primary or benzylic positions. Chapter 3 of this thesis highlights the development of a borane-catalysed reaction towards the synthesis of saturated nitrogen heterocycles, enabled by the B-N/B-H transborylation reaction. Transborylation involves the redistribution of substituents around boron atoms through σ-bond metathesis. This reactivity pathway serves as an alternative turnover mechanism to the fundamental steps of transition-metal catalysed reactions (e.g. oxidative addition, transmetalation, and reductive elimination). This chapter introduces an approach towards the cyclisation of azido-alkenes through tandem hydroboration-cycloalkylation-transborylation reactions facilitated by the HBCy2 catalyst and HBpin turnover reagent. Chapter 3 summarises the scope and limitations of this protocol, with pyrrolidine heterocycles established as easiest to access while azetidines and piperidines remained challenging. In addition, a proof of principle study is presented where enantioenriched borane catalysts, such as Ipc2BH and Soderquist’s borane, were used to cyclise pro-chiral azido-alkene substrates. Overall, the work discussed in this chapter marks a novel entry in the boron-catalysed reaction repertoire enabled by transborylation.