La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia.
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Angew Chem Int Ed Engl. 2019 Mar 26;58(14):4552-4556. doi: 10.1002/anie.201813761. Epub 2019 Feb 27.
SuFEx is a new-generation click chemistry transformation that exploits the unique properties of S-F bonds and their ability to undergo near-perfect reactions with nucleophiles. We report here the first SuFEx-based procedure for the efficient synthesis of pharmaceutically important triflones and bis(trifluoromethyl)sulfur oxyimines from sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new process involves rapid S-F exchange with trifluoromethyltrimethylsilane (TMSCF ) upon activation by potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. A tentative mechanism is proposed involving nucleophilic displacement of S-F by the trifluoromethyl anion via a five-coordinate intermediate. The utility of late-stage SuFEx trifluoromethylation is demonstrated through the synthesis and selective anticancer properties of a bis(trifluoromethyl)sulfur oxyimine.
SuFEx 是一种新一代的点击化学转化，利用 S-F 键的独特性质及其与亲核试剂近乎完美的反应能力。我们在这里报告了第一个基于 SuFEx 的程序，用于从砜和亚磺酰亚胺二氟氧化物分别有效地合成药物上重要的三氟酮和双（三氟甲基）硫代亚硝酰。新工艺涉及在无水 DMSO 中由氟化钾活化后与三氟甲基三甲基硅烷（TMSCF ）快速进行 S-F 交换。该反应耐受广泛的底物选择，并在温和条件下进行，无需进行色谱纯化。提出了一种涉及通过五配位中间体由三氟甲基阴离子对 S-F 进行亲核取代的推测机制。通过合成和选择性抗癌性质的双（三氟甲基）硫代亚硝酰证实了后期 SuFEx 三氟甲基化的实用性。
