Introduction
The development of new fluorination methodologies is driven largely by the beneficial effects of including fluorine into bioactive molecules. These advantages include the modulation of potency, bioavailability and physical properties of drug and agrochemical compounds [1-3]. The significance of fluorination is reflected in the fact that a large number of agrochemicals contain fluorine, and that almost a quarter of drug molecules approved by the FDA between 2018 and 2022 contained at least one fluorine atom, for example belzutifan and quinofumelin, Figure 1A [4,5].
The fluorination of functionalised carbon centres is a reliable strategy to incorporate fluorine into compounds of interest, with regio and site selectivity pre-determined by the nature of the functionalised carbon. However, the development of C(sp3)-H fluorination methods represents a more sustainable and versatile approach, as there is no requirement to pre-functionalise the compound, carry that functional group through synthesis and also protect any potentially labile group that would otherwise displace during the installation of the fluorine atom [6-8]. Therefore, methodologies for the selective C-H fluorination represent a valuable class of reactions [1,9,10], for which several have been disclosed in the chemical literature [11,12].
Benzylic C(sp3)-H bonds are comparatively weaker compared to unactivated C(sp3)-H bonds, with bond dissociation enthalpies (BDEs) falling in the range of 76-90 kcal mol−1 (Figure 1B), due to the increased stability of benzylic radicals and ions imparted through delocalisation with the adjacent π-system [13-15]. In general, the more stabilised the benzylic radical, the weaker the C(sp3)-H bond, as demonstrated when considering the BDEs of a series of phenyl-substituted methanes (Figure 1B). The changes in BDE correlate with the relative stability of primary, secondary and tertiary benzylic radicals and cations. As a result, the presence of benzylic C(sp3)-H bonds in bioactive molecules can be problematic as they are particularly labile to enzymatic oxidation [16], and hence, their functionalisation has become a strategy to overcome this [17]. For this reason, the fluorination of benzylic C(sp3)-H bonds has become particularly important in biologically relevant situations. Benzylic C(sp3)-H bonds are also present in a large portion of commercially available building blocks, highlighting the appeal for benzylic C(sp3)-H functionalisation reactions in drug-discovery campaigns [17]. Although much is unknown about the precise details, several benzylic fluorides have been reported to be unstable, which is an effect that is apparently dependent on the substitution of the ring. While primary benzylic fluorides are predominately considered to be stable to isolation conditions, secondary and tertiary suffer from the elimination of HF, especially in the presence of silica gel or glass vessels. Therefore, benzyl fluorides have been derivatised, for example in C-O, C-N and C-C bond-forming reactions [18-20], thereby also demonstrating their suitability, as precursors for further functionalisation.
Reviews on the broad area of C-H fluorination have been written [11,12,21-29] with the focus varying, for example between aliphatic fluorination [23], α-fluorination of carbonyl compounds [30], photosensitised C-H fluorination [21,26], recent advances [24] and mechanistic approaches [11]. Examples of specifically benzylic C(sp3)-H fluorination reactions are included into many of these reports, as well as in sections of reviews with a much broader scope [12,27,28], and alternative routes to benzylic fluorides have also been reviewed, such as through deoxyfluorination, C-X fluorination, or decarboxylative fluorination [22,31-33]. However, a comprehensive review that focusses specifically on benzylic C-H bonds is still currently missing in the literature. Therefore, we aim to cover reports that focus specifically on benzylic C(sp3)-H fluorination, emphasising the most recent protocols but with also some historical context. We also signpost readers to reports where benzylic C-H fluorination has been included, but is not the focus of the work. We have organised the review into different mechanistic strategies, namely, electrophilic, radical and nucleophilic approaches, and highlighted when emerging technologies, such as photo- and electrochemistry effect the desired transformation [22,27].