New Directions in C–H Fluorination

Abstract

Late-stage C–H fluorination can quickly provide value-added molecules that are not readily available otherwise for applications in pharmaceutical, agrochemical, and materials research and beyond. Direct C–H fluorination has the advantage over the more conventional fluorination by functional group interconversion that target molecules can be accessed without the need for the introduction of additional functional groups. The development of appropriate catalysts that can control reactivity and selectivity is currently a major frontier of the field, in the ideal case making use of inexpensive fluoride sources in combination with a benign, readily available stoichiometric oxidant. One-step transformations from C–H to C–F are attractive methods especially if fluorine can be introduced at a late-stage of the synthesis. However, C–H fluorination is still an unsolved problem with just few successful approaches so far (as opposed to all other halogenation reactions). In this opinion, we highlight the challenges associated with C–H fluorination and discuss current progress for three different classes: directed fluorination, aliphatic fluorination, and aromatic fluorination. One-step transformations from C–H to C–F are attractive methods especially if fluorine can be introduced at a late-stage of the synthesis. However, C–H fluorination is still an unsolved problem with just few successful approaches so far (as opposed to all other halogenation reactions). In this opinion, we highlight the challenges associated with C–H fluorination and discuss current progress for three different classes: directed fluorination, aliphatic fluorination, and aromatic fluorination. the energy required to break a bond and form two atomic or molecular fragments, each with one electron of the original shared pair. benzoquinone and its derivatives; here not only as an oxidant, but also as a ligand for palladium. a process similar to the Chichibabin reaction that is used for the synthesis of 2-aminopyridine by the reaction of pyridine with sodium amide. for a mixture of (+) and (–) enantiomers, with composition given as the mole or weight fractions F(+) and F(–) [where F(+) + F(–) = 1], the enantiomeric excess is defined as |F(+) – F(–)| (and the percent enantiomeric excess by |F(+) – F(–)|×100%) abstraction of a hydrogen atom to generate a radical. direct functionalization of an already densely functionalized molecule. an electrophilic fluorinating reagent. a radiotracer that can provide information about a target in vivo through PET imaging. a procedure in which a small amount of radioactive glucose (sugar) is injected into a vein, and a scanner is used to make detailed, computerized pictures of areas inside the body where the glucose is taken up. Because cancer cells often take up more glucose than normal cells, the pictures can be used to find cancer cells in the body. a directing group that is formed temporarily and reversibly through reaction with a functional group on the substrate.