Click Chemistry‐Enabled Synthesis of Diversely Functionalized Cyclobutenes

Abstract 4‐Membered rings are important structural motifs in many bioactive natural products and pharmaceutically relevant molecules. Further, these strained ring systems serve as versatile precursors for accessing diverse classes of organic compounds. In this study, 1,1‐bis(fluorosulfonyl)‐2‐(pyridin‐1‐ium‐1‐yl)ethan‐1‐ide, a stable ethene‐1,1‐disulfonyl fluoride precursor, is applied to expand the library of highly functionalized cyclobutenes accessible through a [2 + 2] click chemistry cycloaddition pathway. The 29 cyclobutene products were isolated in perfect regioselectivity influenced by the choice of electron‐withdrawing (ester, ketone, sulfone, and sulfonyl fluoride) or electron‐donating groups (chalcogen) on the alkyne, significantly broadening the accessibility of these valuable four‐membered ring systems. The reaction is straightforward to perform, tolerates a wide variety of functional groups, uses mild reaction conditions and requires minimal purification. The potential to diversify the cyclobutene core is demonstrated through sulfur‐fluoride exchange (SuFEx) click chemistry and amide coupling reactions.