Ethene‐1,1‐disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1‐Bissulfonylfluoride Substituted Cyclobutene Hubs

Abstract

We present the synthesis of 1,1-bis(fluorosulfonyl)-2-(pyridin-1-ium-1-yl)ethan-1-ide, a bench-stable precursor to ethene-1,1-disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1-bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase diversification of the novel cyclobutene cores through selective Cs 2 CO 3 -activated SuFEx click chemistry between a single SÀ F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.

Intramolecular Chalcogen Bonding Activated SuFEx Click Chemistry for Efficient Organic-Inorganic Linking

“…The important role of click chemistry in modern science has been recognized by the 2022 Nobel Prize in Chemistry 1,2 . Recently, a new generation of click chemistry, sulfur uoride exchange (SuFEx) promoted by Sharpless, Moses and co-workers, has demonstrated impressive molecular assembly capabilities [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] .…”

“…Bene ted from the diverse collection of SuFExable hubs 3,[7][8][9][10][11][12][13][14] , SuFEx chemistries offer tremendous scope for exploring chemical space and wide range of sulfuryl-heteroatom connectors to meet more diverse linking needs, thus enabling its rapid development as the technology of choice in organic synthesis [18][19][20] , drug discovery [21][22][23] , chemical biology 24,25 and polymer chemistry [26][27][28] (Fig. 1a).…”