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revised on 04.12.2018 and posted on 04.12.2018by 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
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.