Herein, a water‐accelerated, N‐heterocyclic carbene (NHC)‐catalyzed aza‐Michael addition reaction was reported to access β‐aminosulfonyl fluorides, which are key hubs of the sulfur(VI) fluoride exchange (SuFEx) reaction. As a crucial reaction medium, water considerably enhanced the reaction rate with excellent chemo‐ and site‐selectivity (up to >99 : 1) compared to conventional solvents. In addition, the late‐stage ligation of bioactive molecules with the aliphatic β‐amino SuFEx hub was demonstrated. Mechanistic studies on experimental, analytical, and computational approaches support noncovalent activation over NHC catalysis “on‐water”.
β‐Sulfido sulfonyl fluoride and its derivatives have been gaining attention recently in the fields of medicinal chemistry and material science. The conventional method for the synthesis of functionalized alkyl sulfonyl fluorides requires several chemical transformations. Therefore, a direct establishment of such chemical structures remains challenging, and an efficient catalytic approach is highly desired. Herein a significant “on‐water” hydrophobic amplification was achieved, enabling a high‐turnover catalytic thia‐Michael addition to produce unprecedented β‐arylated‐β‐sulfido sulfonyl fluorides. Amounts as low as 100 ppm (0.01 mol %) of the phosphazene superbase were sufficient to successfully catalyze the reaction with excellent chemo‐/site‐selectivity and with optimal functional group tolerance. Several β‐arylated ethene sulfonyl fluorides were converted into thia‐Michael adducts up to >99 % yields. The mild conditions, high turnover, neutral pH, and scalability of the sustainable catalytic process benefit the preparation of potential pharmaceuticals (e. g., polyisoprenylated methylated protein methyl esterase inhibitors) and organic materials (e. g., electrolyte additives).
In this account, we provide an overview of the recent achievements through our research programs focusing on sustainable organocatalysis. Our group have unveiled the effectiveness of specific organocatalysts in various environmentally benign conditions. We found that 1) N-heterocyclic carbene and 2) phosphazene superbases exhibit favorable performance in bulk aqueous reaction environments. In addition, 3) using organic superacid catalysts resulted in synergistic effects when hydrogen-bond donor catalysts were assembled under aqueous media. Moreover, we discovered that 4) a neutral organic salt precatalyst can generate a potent silylium Lewis acid catalyst in situ, specifically under solvent-free conditions. These innovative sustainable organocatalytic processes have successfully facilitated the conversion of raw starting materials into valuable compounds, including sulfur (VI) fluoride exchange (SuFEx) click hubs and tetrasubstituted carbon centers incorporating heteroatoms.
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