β‐Aminosulfonyl Fluorides via Water‐Accelerated N‐Heterocyclic Carbene Catalysis

Abstract

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”.

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…Nevertheless, reported examples of sulfonyl fluoride reaction with Onucleophiles demonstrate selectivity of this reaction in presence of ester, [26,[203][204][205][206] alkyl halide (Cl [26] or Br [145] ), chalcone, [207] and oxetane ring (Scheme 33). [208] Other notable functional groups that showed tolerance to the above conditions include enolizable ketones, [152,153] adenine, [209] unprotected aniline, [65] and sometimes even free alcohol [210] fragments.…”

“…Being a strong electron‐withdrawing group, the SO 2 F fragment is considered as one of the best double bond activators for the nucleophilic conjugate (Michael) addition [60] . Indeed, alkenyl sulfonyl fluorides readily react with a huge variety of C ‐, [60–64] N ‐, [43,62,64–67] S ‐, [25,64,67,68] or P ‐nucleophiles [69] (Scheme 4). For example, Michael addition to the simplest vinyl sulfonyl fluoride was used for the preparation of [ 18 F]‐labelled amino acids [70] and modification of s ‐tetrazine building blocks [71] .…”

Sustainable Organocatalytic Processes to Access Alkyl SuFEx Click Hubs and Tetrasubstituted Carbon Centers: Potential Libraries for Multidisciplinary Applications

“…catalysis for β-aminosulfonyl fluorides 8 SuFEx click chemistry, a potentially new class of click chemistry that was revitalized by Sharpless et al, 9 has received tremendous attention for ligating sulfur(VI)-centered electrophiles with various oxygen-and nitrogen-containing nucleophiles. In this manner, the sulfonyl fluoride (-SO2F) group has been considered a useful hub in multidisciplinary science fields such as organic chemistry, drug discovery, and materials science by establishing building blocks through the linkage of each molecule.…”

“…The preparation of -aminosulfonyl fluorides was accomplished through a water-accelerated, N-heterocyclic carbene (NHC) SIMes-catalyzed aza-Michael addition reaction. 8 Though catalytic reactions utilizing NHCs have been well-established in recent decades, NHCs as water-compatible organic promoters have rarely been reported. 11 In addition, achieving sulfonyl fluoride tolerance in NHC catalysis was very difficult due to direct cyclization via a Breslowtype covalent intermediate (e.g., sultonization of sulfonyl fluoride was reported by Lupton et al).…”

Alkyl Sulfonyl Fluorides Incorporating Geminal Dithioesters as SuFEx Click Hubs via Water-Accelerated Organosuperbase Catalysis

“…Our group have recently shown that hydrophobic Brønsted superacid "on-water" can significantly enhance the reactivity in multicomponent allylboration. 12 In contrast, in SuFEx-relevant chemistry, Brønsted base catalysis to introduce heteroatom nucleophiles works adequately in thia-and aza-Michael addition reactions by using a phosphazene base catalyst (sulfur nucleophile) 13 and an N-heterocyclic carbene catalyst (nitrogen nucleophile), 14 respectively (the fourth scheme). However, exploiting carbon nucleophiles in this strategy is unknown.…”