SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates

• Published in: Chemical science (Cambridge) 2022-02, Vol.13 (8), p.227-2279
• Main Authors: Li, Bing-Yu, Voets, Lauren, Van Lommel, Ruben, Hoppenbrouwers, Fien, Alonso, Mercedes, Verhelst, Steven H. L, De Borggraeve, Wim M, Demaerel, Joachim
• Format: Article
• Language: English
• Subjects: Amines; Chemical reactions; Chemistry; Coupling (molecular); Esters; Fluorides; Phenols; Telescoping
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d1sc06267k

Sulfur( vi ) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the ex situ generation of trifluoromethanesulfonyl fluoride (CF 3 SO 2 F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the S VI -F connector with a S&z.dbd;O → S&z.dbd;NR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H 2 O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols vs. amine groups, a phenomenon best explained-using ab initio metadynamics simulations-by a hydrogen bonded termolecular transition state for the CF 3 SO 2 F triflylation of amines. Triflyl fluoride gas (CF 3 SO 2 F) and its aza analogues are reported as new SuFEx activators. These S VI -F reagents react efficiently with a variety of nucleophiles, yet the presence of water grants complete chemoselectivity to phenols.