Bifluoride Ion Catalyzed Late-Stage SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

Smedley, Christopher J, Gao, Bing, Li, Suhua, Zheng, Qinheng, Molino, Andrew, Duivenvoorden, Hendrika M, Parker, Belinda S, Wilson, David JD, Sharpless, K Barry, Moses, John E (November 2018) Bifluoride Ion Catalyzed Late-Stage SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides. (Submitted)

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DOI: 10.26434/chemrxiv.7312595.v2


Sulfur-Fluoride Exchange (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 protocol for the efficient late-stage synthesis of pharmaceutically important trifluoromethyl sulfones and bis(trifluoromethyl)sulfur oxyimines from the corresponding sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new protocol involves the rapid exchange of the S-F bond with trifluoromethyltrimethylsilane (TMSCF3, Ruppert’s reagent), upon activation with catalytic potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. DFT calculations provide the first reported mechanism of anhydrous SuFEx reactivity, which confirms catalytic bifluoride behaviour with a five-coordinate sulfur intermediate. The preparation of a benzothiazole derived bis(trifluoromethyl)sulfur oxyimine with cytotoxic selectivity for MCF7 breast cancer cells demonstrates the utility of this methodology for the late stage functionalization of bioactive molecules.

Item Type: Paper
Subjects: chemistry > techniques > click chemistry > Accelerated SuFEx Click Chemistry
chemistry > techniques > click chemistry
CSHL Authors:
Communities: CSHL labs > Moses lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 15 November 2018
Date Deposited: 13 Oct 2023 18:29
Last Modified: 13 Oct 2023 18:29
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