Design of unprecedented electrophilic SF5 reagents: applications in the synthesis of heteroatom-SF5/carbon-SF5 bonds and late-stage functionalization

The Give-Me-Five project will provide the next generation of fluorinated molecules that found plethora of applications in life science. Currently up to 50% of agrochemicals as well as 20% of pharmaceuticals contain a fluorinated motif. As an example, the trifluoromethyl (CF3) group is one of the most used fluorinated motifs in research and development.

Although several research programs have been dedicated to the synthesis of CF3-molecules with numerous CF3-reagents being developed, recent reports pointed out a major stability drawback of the CF3 moiety impacting its usefulness. Thus, developing more stable fluorinated motifs that could replace the CF3 group is urgent.

In this context, pentafluorosulfanyl (SF5) motif is considered as a “super trifluoromethyl motif” since it is more stable than the CF3 motif.

However, two major drawbacks should be overcome to unlock the potential of SF5 molecules: (i) current direct methodologies to introduce the SF5 motif rely on scarcely commercially available and highly toxic SF5Cl – a SF5 radical precursor, and (ii) this precursor features a very limited reactivity.

Although the availability and toxicity concerns have been recently addressed in my lab by developing an in situ protocol to generate and use SF5Cl, the problem of poor reactivity remains.

Here, I propose to tackle this challenge by designing new, more sustainable and stable electrophilic SF5 sourcesTo provide the first general direct synthesis of SF5-molecules we will:1. Synthesize the first shelf-stable family of reagents prone to be SF5 electrophile donor 2. Apply the new shelf-stable reagents to forge heteroatom-SF5 bonds3.

Develop a copper catalyzed approach to forge C-SF5 bonds using our shelf-stable reagents This endeavour could provide the first direct general synthesis of SF5-molecules, paving the way to the next generation of fluorinated molecules. Hence, it will foster developments of agrochemical, pharmaceutical as well as material containing SF5 motif