A Sulfonative rearrangement of N-aryl sulfamates to para-sulfonyl anilines

Yifei Zhou, Alan M Jones

Research output: Working paper/PreprintPreprint


The C(sp2)-aryl sulfonate functional group is widely found in bioactive scaffolds but can often only be accessed under forcing temperatures (>190 °C) and corrosive reaction conditions. Inspired by the Tyrer process to sulfa dyes that involves an aniline N(sp2)-SO3 intermediate en route to a C(sp2)-SO3 rearranged product - we deployed tributylsulfoammonium betaine (TBSAB) as an initiating mild sulfamating agent to sulfonate relay reagent. A range of aniline and heterocyclic scaffolds were sulfonated in high conversions (6 examples of N(sp2)-sulfamates up to 99% isolated yield and 16 examples of C(sp2)-sulfonate in up to 80% isolated yield) with the ability to change the ortho-para selectivity of the products obtained under thermal control. Isolation of the N(sp2)-SO3 intermediates for a two-step procedure was significantly lower yielding than a direct one-pot procedure. Furthermore, we explore counterion effects on the N- to C- sulfate rearrangement and discovered the reversibility of the TBSAB reagent. Investigation of the N- to C- mechanism through designed examples with variation at the heteroatom position, and kinetic isotope experiments (KIEH/D) confirmed the formation of a key N(sp2)-SO3 intermediate and further supporting evidence of an intermolecular mechanism. Compounds without an accessible nitrogen (or hydroxyl) lone pair did not undergo sulfonation under these reaction conditions.
Original languageEnglish
Publication statusPublished - 30 Jun 2022


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