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Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides

preprint
revised on 04.12.2018 and posted on 04.12.2018 by Christopher J. Smedley, Bing Gao, Suhua Li, Qinheng Zheng, Andrew Molino, Hendrika M. Duivenvoorden, Belinda S. Parker, David J. D. Wilson, K. Barry Sharpless, John E. Moses
Sulfur-Fluoride Exchange (SuFEx) is the new generation click chemistry transformation exploiting 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 synthesis of pharmaceutically important triflones 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) upon activation with 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 catalytic mechanism is proposed supported by DFT calculations, involving formation of the free trifluoromethyl anion followed by nucleophilic displacement of the S-F through a five-coordinate 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.

Funding

Developing next generation click chemistry

Australian Research Council

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Sulfur(VI) Fluoride Exchange (SuFEx): new developments and biological applications

National Institute of General Medical Sciences

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History

Email Address of Submitting Author

J.Moses@latrobe.edu.au

Institution

La Trobe University

Country

Australia

ORCID For Submitting Author

0000-0003-2162-3234

Declaration of Conflict of Interest

No conflict of interest

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