Amine-Catalyzed Copper-Mediated C–H Sulfonylation of Benzaldehydes via a Transient Imine Directing Group



Transient directing groups can provide a powerful means for C–H functionalization to install medicinally valuable motifs without requiring additional steps for directing group introduction and removal. Here we report the first use of a transient directing group in combination with copper to effect C-H functionalization. The copper mediated β–C(sp2)–H sulfonylation of aldehydes with sulfinate salts is accomplished using β-alanine, in catalytic quantities, to form a transient imine. A broad range of sulfonylated benzaldehydes are prepared using copper fluoride as both copper source and oxidant, involving a [5,6] cupracyclic intermediate. The transient directing group provides exclusive regioselectivity in C–H functionalization, even in the presence of other strongly coordinating Lewis basic groups. In addition, gamma-(peri)-sulfonylation of napthyl and phenanthrene carboxaldehydes is achieved through [6,6] cupracyclic intermediates. Further derivatisation of the aldehyde products is demonstrated. Mechanistic studies, including deuteration and kinetic experiments, which identify orders in all reagents, provide insight to the catalytic behaviour of the amine. Kinetic isotope effect experiments and Hammett analysis suggest the turnover limiting step to be a concerted asynchronous C–H cleavage via a dearomative Wheland-type transition state.

Version notes

- The introduction has included more on the synthesis and utility of sulfones. - New examples of reaction scope have been included have been added, showing the tolerance of the reaction to coordinating and potentially sensitive functionalities - a range of derivatisation reactions have been added to exemplify use of the available aldehyde functionality - Discussions on the mechanism of this reaction has been expanded. - Title has been changed. - Schemes have been modified and improved.


Supplementary material

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Supporting information for Amine-Catalyzed Copper-Mediated C–H Sulfonylation of Benzaldehydes via a Transient Imine Directing Group