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

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. Amongst these, sulfonyl fluorides have emerged as the work-horse 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 proven 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.

Photoredox catalytic radical fluorosulfonylation of olefins enabled by a bench-stable redox-active fluorosulfonyl radical precursor

“…Since Sharpless and co-workers introduced sulfur (VI) fluoride exchange (SuFEx) reactions as a new generation of click chemistry 1 , the popularity of sulfonyl fluorides has grown dramatically over the recent past 1 – 4 , with applications in a wide range of fields, including organic synthesis 5 – 10 , polymer preparation 11 – 14 , materials science 15 – 17 , chemical biology etc 18 – 20 . Particularly, unique and appealing properties were often observed, which has attracted a fast-growing research interest on sulfonyl fluoride being a privileged warhead in chemical biology and drug discovery 1 , 4 , 18 , and successful examples keep emerging in the past years 18 – 27 .…”

Scalable, Chemoselective Nickel Electrocatalytic Sulfinylation of Aryl Halides with SO2

“…To simplify the isolation and quantification of the e‐sulfinylation reaction, sulfinates were converted in situ into the stable sulfonyl fluorides. Sulfonyl fluorides are a versatile functional group, capable of SuFEx Click chemistry, [58, 59] acting as a covalent warhead in protein inhibitors, [60–62] and as synthetic intermediates to other S VI derivatives [42, 43, 63–69] . The fluorination was optimized and performed in the same pot after sulfinylation, using inexpensive TBAF and N ‐chlorosuccinimide (NCS).…”

“…Sulfonyl fluorides are a versatile functional group, capable of SuFEx Click chemistry, [58,59] acting as a covalent warhead in protein inhibitors, [60][61][62] and as synthetic intermediates to other S VI derivatives. [42,43,[63][64][65][66][67][68][69] The fluorination was optimized and performed in the same pot after sulfinylation, using inexpensive TBAF and N-chlorosuccinimide (NCS).…”

Fluorosulfonyl radicals: new horizons for the synthesis of sulfonyl fluorides

“…1). 1 Since the concept of Sulfur( vi ) Fluoride Exchange (SuFEx) was pioneered by Sharpless and co-workers as the next generation of click chemistry in 2014, 2 sulfonyl fluorides have received considerable attention and continuous interest from the communities of synthetic chemistry and medicinal chemistry. Generally, strategies for the construction of these frameworks mainly focus on the fluoride–chloride exchange from the corresponding sulfonyl chlorides.…”