Abstract
Sulfonyl fluorides are valuable synthetic motifs which are currently of high interest due to the popularity of the sulfur (VI) fluoride exchange (SuFEx) click chemistry concept. Herein, we describe a flow chemistry approach to enable their synthesis through an electrochemical oxidative coupling of thiols and potassium fluoride. The reaction can be carried out at room temperature and atmospheric pressure and the yield of the targeted sulfonyl fluoride, by virtue of the short inter-electrode distance between a graphite anode and a stainless-steel cathode, reached up to 92% in only 5 min residence time compared to 6 to 36 h in batch. A diverse set of thiols (7 examples) was subsequently converted in flow. Finally, a fully telescoped process was developed which combines the electrochemical sulfonyl fluoride synthesis with a follow-up SuFEx reaction.
Highlights
Click chemistry is a popular synthetic concept which enables the quick and reliable stitching of two molecular building blocks in high yield and selectivity
Lower yields for the target product were obtained in other common organic solvents, such as THF or methanol (Table 2, Entries 6–7)
The presence of acid provided in general higher yields compared to non-acidic reaction mixtures (Table 2, Entry 1)
Summary
Click chemistry is a popular synthetic concept which enables the quick and reliable stitching of two molecular building blocks in high yield and selectivity. The synthesis of azides has been reported by many research groups and has been successfully coupled with the follow-up Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) [6,7,8,9,10] The combination of these two steps leads to a significant time reduction and keeps the total inventory of hazardous azides low, effectively reducing the safety risks associated with these reagents [11]. The reduced reaction time can be attributed to (i) the increased electrode surface-to-volume ratio, (ii) a high interfacial area between the organic and aqueous phase, and (iii) intensified mass transport due to multiphase fluid patterns. In this manuscript, we provide a full investigation of all relevant process parameters in the flow-enabled
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