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

Introduction

The Give-Me-Five project will provide the next generation of fluorinated molecules that found a plethora of applications in life science. Currently, up to 50% of agrochemicals as well as 20% of pharmaceuticals contain a fluorinated motif.

Importance of Fluorinated Motifs

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.

Need for Stable Alternatives

Thus, developing more stable fluorinated motifs that could replace the CF3 group is urgent. In this context, the pentafluorosulfanyl (SF5) motif is considered a “super trifluoromethyl motif” since it is more stable than the CF3 motif.

Challenges to Overcome

However, two major drawbacks should be overcome to unlock the potential of SF5 molecules:

1. Current direct methodologies to introduce the SF5 motif rely on scarcely commercially available and highly toxic SF5Cl – a SF5 radical precursor.
2. This precursor features 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.

Proposed Solutions

Here, I propose to tackle this challenge by designing new, more sustainable and stable electrophilic SF5 sources.

Objectives

To 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 donors.
2. Apply the new shelf-stable reagents to forge heteroatom-SF5 bonds.
3. Develop a copper-catalyzed approach to forge C-SF5 bonds using our shelf-stable reagents.

Conclusion

This endeavor 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 the SF5 motif.