Remote Fluorination and Fluoroalkyl(thiol)ation Reactions

Abstract

Remote functionalization reactions have the power to transform a C−H (or C−C) bond at a distant position from a functional group. This Review summarizes recent advances and key breakthroughs in remote fluorination, trifluoromethylation, difluoromethylation, trifluoromethylthiolation, and fluoroalkenylation reactions. Several powerful strategies have emerged to control the reactivity and distal selectivity such as the undirected radical approach, the 1,5‐hydrogen atom transfer, the metal migration, the use of distant directing groups, and the ring‐opening reactions. These unconventional and predictable C−H (and C−C) functionalization transformations should allow for the preparation of a wide range of otherwise‐difficult‐to‐access alkyl, aromatic, heteroaromatic, and structurally complex fluorides.

Photocatalytic C–H Trifluoromethylthiolation by the Decatungstate Anion

“…This surge in interest results from the motif’s significant electronegativity and particularly high lipophilicity (Hansch parameter of π = 1.44), which makes the SCF 3 group a powerful handle to both adjust pharmacokinetic properties and optimize interactions of an active compound with its target . While the recent development of tailored reagents has allowed for both polar and radical transformations for the incorporation of the SCF 3 group, use of HAT in this context is of particular interest due to its ability to selectively promote late-stage incorporation of the functionality with relatively high levels of chemoselectivity. The power of such a strategy has been demonstrated by the Glorius group using a dual catalytic system, consisting of an iridium photo- and benzoate HAT-catalyst for the selective trifluoromethylthiolation of methine and formyl C–H bonds (Scheme A) .…”

Distal Construction of a Carbon‐SCF2R Bond on Aliphatic Alcohols Enabled by 1,5‐Hydrogen‐Atom Transfer

“…The development of new tools for the direct functionalization of C−H bond offers original synthetic pathways to reach high molecular complexity and challenging compounds in a step economical manner. Among the possible synthetic solutions to carry out the challenging distal C−H functionalization of aliphatic molecules, straightforward and original strategies [8] based on a 1,5‐HAT or the β‐fragmentation of constrained rings were designed and applied to access fluorinated molecules [9,10] . Although the 1,5‐HAT strategy has mainly focused on the remote fluorination and trifluoromethylation reactions, [9,10] only a handful of reports deal with the distal C−H functionalization with a SCF 3 moiety and a unique report regarding the SCF 2 H residue has yet been depicted.…”

Multiple-fold C–F bond functionalization for the synthesis of (hetero)cyclic compounds: fluorine as a detachable chemical handle

“…As a Danhua Ge result, the past decades have witnessed an enormous emergence of new synthetic methodologies for the facile introduction of fluorinated functionalities into various prime skeletons. [4][5][6][7][8][9] On the other hand, many simple multifluorocarbons such as perfluoroalkyl halides (PFHs), perfluorinated carboxylic acids (PFCAs), and perfluorinated sulfonic acids (PFSAs) are important bulk chemicals and commercially available on an industrial scale. In the meantime, the extensive utilities of poly-or perfluorinated compounds (PFCs) since the 1940s have led to a worldwide pollution problem.…”