The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium‐modified drugs directly from their non‐labeled parents. While most of the recent studies focus on metal‐catalyzed C−H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late‐stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures.
Through superacid activation, N-(arenesulfonyl)-aminoalcohols derived from readily-available ephedrines or amino acids undergo an intramolecular Friedel-Crafts reaction to afford enantiopure benzosultams bearing two adjacent stereocenters in high yields with a fully-controlled diastereoselectivity. Low-temperature NMR spectroscopy demonstrated the crucial role played by the conformationally-restricted chiral dicationic intermediates.
Under
superacidic conditions, aniline and indole derivatives are
sulfonylated at low temperature with easy-to-access arenesulfonic
acids or arenesulfonyl hydrazides. By modification of the functional-group
directing effect through protonation, this method allows nonclassical
site functionalization by overcoming the innate regioselectivity of
electrophilic aromatic substitution. This superacid-mediated sulfonylation
of arenes is complementary to existing methods and can be applied,
through protection by protonation, to the late-stage site-selective
functionalization of natural alkaloids and active pharmaceutical ingredients.
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