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Sulfonyl fluorides as targets and substrates in the development of new synthetic methods

Nature Reviews Chemistry volume 6, pages 146–162 (2022)Cite this article

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Abstract

The advent of sulfur(vi)-fluoride exchange (SuFEx) processes as transformations with click-like reactivity has invigorated research into electrophilic species featuring a sulfur–fluorine bond. Among these, sulfonyl fluorides have emerged as the workhorse functional group, with diverse applications being reported. Sulfonyl fluorides are used as electrophilic warheads by both medicinal chemists and chemical biologists. The balance of reactivity and stability that is so attractive for these applications, particularly the resistance of sulfonyl fluorides to hydrolysis under physiological conditions, has provided opportunities for synthetic chemists. New synthetic approaches that start with sulfur-containing substrates include the activation of sulfonamides using pyrilium salts, the deoxygenation of sulfonic acids, and the electrochemical oxidation of thiols. Employing non-sulfur-containing substrates has led to the development of transition-metal-catalysed processes based on palladium, copper and nickel, as well as the use of SO2F2 gas as an electrophilic hub. Selectively manipulating molecules that already contain a sulfonyl fluoride group has also proved to be a popular tactic, with metal-catalysed processes again at the fore. Finally, coaxing sulfonyl fluorides to engage with nucleophiles, when required, and under suitable reaction conditions, has led to new activation methods. This Review provides an overview of the challenges in the efficient synthesis and manipulation of these intriguing functional groups.

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Fig. 1: Background of sulfonyl fluoride functional group.
Fig. 2: Different established routes to the preparation of sulfonyl fluorides.
Fig. 3: Accessing various sulfonyl-containing functional groups from sulfonyl fluorides through SuFEx.
Fig. 4: Multifunctional sulfonyl fluoride reagents and their applications.
Fig. 5: Applications of sulfonyl fluorides in organic synthesis (parts a–c) and materials chemistry (parts d–f).
Fig. 6: Applications of SFs in chemical biology.
Fig. 7: Applications of SFs in 18F-radiolabelling.

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  1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

    Terry Shing-Bong Lou & Michael C. Willis

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Glossary

Bactericidal

Having the ability to kill bacteria, as compared to ‘bacteriostatic’ which inhibits bacterial growth or reproduction.

LD50

Median lethal dose, the dose required to kill half of the sample population, expressed as the mass of chemical administered per body mass of test subject.

Click reactions

Thermodynamically favoured processes of joining modular building blocks, which are highly selective, high-yielding, operationally simple and insensitive to oxygen and water.

Ionic liquids

Salts that are liquid at temperatures below 100 °C.

Activity-based protein probes

Small molecules composed of a functional group capable of binding with target proteins, and a second reactive site (reporter) for protein analysis or transformation.

Positron emission tomography

(PET). An imaging technique used in nuclear medicine that measures the metabolic activity of the cells of body tissues, through the administration of a radiotracer.

Passivation

Formation of a coating on a material that is more inert than the material itself.

Ionomer

A polymer that consists of electrically neutral repeating units and a fraction of ionized units distributed along the polymer backbone.

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Lou, T.SB., Willis, M.C. Sulfonyl fluorides as targets and substrates in the development of new synthetic methods. Nat Rev Chem 6, 146–162 (2022). https://doi.org/10.1038/s41570-021-00352-8

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