Radical fluorination is a type of fluorination reaction, complementary to nucleophilic and electrophilic approaches. It involves the reaction of an independently generated carbon-centered radical with an atomic fluorine source and yields an organofluorine compound.
Contents
- Decarboxylative fluorination
- Radical fluorination of alkenes
- Fluorination of boronic acid derivatives
- Csp3H fluorination
- CC bonds activation
- Potential application
- References
Historically, only three atomic fluorine sources were available for radical fluorination: Fluorine (F2), hypofluorites (O—F based reagents) and XeF2. Their high reactivity, and the difficult handling of F2 and the hypofluorites, limited the development of radical fluorination compared to electrophilic and nucleophilic methods. The uncovering of the ability of electrophilic N—F fluorinating agents to act as atomic fluorine source led to a renaissance in radical fluorination.
Various methodologies have since been developed for the radical formation of C—F bonds. The radical intermediates have been generated from carboxylic acids and boronic acid derivatives, by radical addition to alkenes, or C—H bond and C—C bond activations. New sources of atomic fluorine are now emerging, such as metal-fluoride complexes.
Decarboxylative fluorination
Thermolysis of t-butyl peresters has been used to generate alkyl radicals in presence of NFSI and Selectfluor. The radicals intermediates were efficiently fluorinated, demonstrating the ability of the two electrophilic fluorinating agents to transfer fluorine to alkyl radicals.
Carboxylic acids can be used as radical precursors in radical fluorination methods. Metal catalysts such as silver and manganese have been used to induce the fluorodecarboxylation. The fluorodecarboxylation of carboxylic acids can also be triggered using photoredox catalysis. More specifically, phenoxyacetic acid derivatives have been shown to undergo fluorodecarboxylation when directly exposed to UV-light irradiation or via the use of a photosensitizer.
Radical fluorination of alkenes
Alkyl radicals generated from radical additions to alkenes have also been fluorinated. Hydrides and nitrogen-, carbon-, and phosphorus-centered radicals have been employed, yielding a wide range of fluorinated, difunctionalized compounds.
Fluorination of boronic acid derivatives
Alkyl fluorides have been synthesized via radicals generated from boronic acid derivatives using silver.
C(sp3)—H fluorination
One major advantage of radical fluorination is that it allows the direct fluorination of remote C—H bonds. Metal catalysts such as Mn, Cu or W have been used to promote the reaction. Metal-free C(sp3)—H fluorinations rely on the use of radical initiators (Et3B, persulfates or N-oxyl radicals) or organic photocatalysts.
Some methods have also been developed to selectively fluorinate benzylic C—H bonds.
C—C bonds activation
Cyclobutanols and cyclopropanols have been used as radical precursors for the synthesis of β- or γ-fluoroketones. The strained rings undergo C—C bond cleavage in presence of a silver or an iron catalyst or when exposed to UV-light in presence of a photosensitizer.
Potential application
One potential application of radical fluorination is for efficiently accessing novel moieties to serve as building blocks in medicinal chemistry. Derivatives of propellane with reactive functional groups, such as the hydrochloride salt of 3-fluorobicyclo[1.1.1]pentan-1-amine, are accessible by this approach.