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

Abstract

The C(sp2)-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(sp2)-SO3 intermediate en route to a C(sp2)-SO3 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(sp2)-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 (KIEH/D) confirmed the formation of a key N(sp2)-SO3 intermediate and further confirmed an intermolecular 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(sp2)-sulfamates (O(sp2)-sulfates) and C(sp2)-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.

A General Method to Access Underexplored Ylideneamino Sulfates as Interrupted Beckmann-Type Rearrangement Intermediates

“…A series of complexing agents (pyridine, dioxane, triethyl phosphate, DMF) with sulfur trioxide have been explored to prepare caprolactam via the O-sulfate and subsequent treatment with aqueous sodium hydroxide [24]. Inspired by these findings in Scheme 1, we initially considered whether tributylsulfoammonium betaine (TBSAB) [25][26][27][28][29][30] would be an effective sulfation reagent for the generation of O-sulfated oximes (ylideneamino sulfates), a functional group with a paucity of methods to tractably access [31]. It was anticipated that these ylideneamino sulfates could act as intercepted Beckmann rearrangement intermediates [15].…”

“…Inspired by these findings in Scheme 1, we initially considered whether tributylsulfoammonium betaine (TBSAB) [25][26][27][28][29][30] would be an effective sulfation reagent for the generation of O-sulfated oximes (ylideneamino sulfates), a functional group with a paucity of methods to tractably access [31]. It was anticipated that these ylideneamino sulfates could act as intercepted Beckmann rearrangement intermediates [15].…”