Benzamides are an important medicinal motif present in over 100 approved drugs but often suffer from poor physiochemical properties such as low solubility due to their planar structure. Hence, bioisosteres of benzamides are also common, but are significantly harder to access synthetically (Figure 1).¹ Aryl amino-oxetanes are promising, more 3-dimensional bioisosteric candidates for benzamides but remain uninvestigated due to a dearth of synthetic methods. Sulfonyl fluorides have emerged as popular click reagents that react with nucleophiles in a Sulfur–Fluoride Exchange reaction (SuFEx) to generate S(VI)-derivatives such as sulfonamides and sulfonate esters.²

This presentation will describe an alternative defluorosulfonylation reaction of oxetane sulfonyl fluorides (OSF) to generate aryl amino-oxetanes as isosteres of benzamides (Figure 2).³ Instead of reacting in a SuFEx fashion, OSFs liberate SO₂ and fluoride upon warming to generate an oxetane carbocation. This disconnection mimics classic amide couplings and thus, allows the direct use of the vast amine libraries available to pharmaceutical companies. The transformation was showcased through a wide scope, the functionalization of amine-containing drugs, the synthesis of 10 oxetane analogues of benzamide drugs and the generation of a compound library by an array screen. Kinetic and computational experiments support the formation of a planar oxetane carbocation by an S_N1 mechanism.