Rearrangement of Arylsulfamates and Sulfates to Para -Sulfonyl Anilines and Phenols.

The C (sp 2 )-aryl sulfonate functional group is found in bioactive molecules, but their synthesis can involve extreme temperatures (>190 °C or flash vacuum pyrolysis) and strongly acidic reaction conditions. Inspired by the 1917 Tyrer industrial process for a sulfa dye that involved an aniline N (sp 2 )-SO 3 intermediate en route to a C (sp 2 )-SO 3 rearranged product, we investigated tributylsulfoammonium betaine (TBSAB) as a milder N -sulfamation to C -sulfonate relay reagent. Initial investigations of a stepwise route involving TBSAB on selected anilines at room temperature enabled the isolation of N (sp 2 )-sulfamate. Subsequent thermal rearrangement demonstrated the intermediary of a sulfamate en route to the sulfonate; however, it was low-yielding. Investigation of the N -sulfamate to C --sulfonate mechanism through control experiments with variation at the heteroatom positions and kinetic isotope experiments (KIE H/D ) confirmed the formation of a key N (sp 2 )-SO 3 intermediate and further confirmed an inter molecular mechanism. Furthermore, compounds without an accessible nitrogen (or oxygen) lone pair did not undergo sulfamation- (or sulfation) -to-sulfonation under these conditions. A one-pot sulfamation and thermal sulfonation reaction was ultimately developed and explored on a range of aniline and heterocyclic scaffolds with high conversions, including N (sp 2 )-sulfamates ( O (sp 2 )-sulfates) and C (sp 2 )-sulfonates, in up to 99 and 80% (and 88% for a phenolic example) isolated yield, respectively. Encouragingly, the ability to modulate the ortho-para selectivity of the products obtained was observed under thermal control. A sulfonated analog of the intravenous anesthetic propofol was isolated (88% yield), demonstrating a proof-of-concept modification of a licensed drug alongside a range of nitrogen- and sulfur-containing heterocyclic fragments used in drug discovery.