Abstract
The importance of fluorinated products in pharmaceutical and medicinal chemistry has necessitated the development of synthetic fluorination methods, of which direct C–H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C–H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal catalysis and photochemistry. Where transition metal catalysis provides one strategy for C–H bond activation, transition-metal-free photochemical C–H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods. One exciting development in C–F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this review, we highlight photosensitized C–H fluorination as a recent strategy for the direct and remote activation of C–H (especially C(sp3)–H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of reactions.
Highlights
Where transition metal catalysis provides one strategy for C–H bond activation, transition-metal-free photochemical C–H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods
1.1 Importance of direct C–H fluorination/ trifluoromethylation and photosensitization in organic synthesis 1.1.1 Importance of fluorine atoms in organic molecules: Here, we briefly summarize the importance of fluorine atoms in organic molecules in the context of medicinal chemistry, materials chemistry, analytical chemistry and in the mechanistic studies of synthetic reactions
We presented an account of PS TTET as an emerging and important method for the direct fluorination and trifluoromethylation of unactivated C–H bonds
Summary
1.1 Importance of direct C–H fluorination/ trifluoromethylation and photosensitization in organic synthesis 1.1.1 Importance of fluorine atoms in organic molecules: Here, we briefly summarize the importance of fluorine atoms in organic molecules in the context of medicinal chemistry, materials chemistry, analytical chemistry and in the mechanistic studies of synthetic reactions. The trifluoromethyl group was recently identified as a bioisostere for the nitro (NO2) group, which is important due to the strong binding ability of the nitro group and the high reactivity, which is speculated to raise toxicity issues [15] Despite their similar size to hydrogen atoms, fluorine atoms possess a very different chemical reactivity and exert very different influences on neighboring atoms. C–H/C–F substitution strongly decreases the basicity of neighboring amines (and lowers the pKa by a similar increment) due to the σ-inductive effect of F This results in i) a higher oral bioavailability [19], ii) a potential liability for phospholipidosis [20], iii) an increased membrane permeability [21] and iv) the mitigation of undesired binding to the human ether a-go-go-related gene (hERG) K+ channel associated with cardiovascular toxicity [22].
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