A Modular Synthesis of C5-Sulfenyl Thiazoles via an Intermolecular Pummerer Rearrangement: An Underexplored Scaffold for Medicinal Chemistry.

The introduction of sulfur substituents to heterocyclic cores in fragments and drugs is hugely advantageous, improving key pharmacokinetic properties, providing additional vectors for synthetic elaboration, and potentially enhancing binding affinities. Despite this potential and their prevalence in drug discovery, sulfur-substituted thiazole scaffolds remain largely underexplored due to synthetic challenges in their preparation. To overcome the limitations in accessing these motifs, we report a mild, modular strategy for assembling C5-sulfenyl thiazoles from β-keto sulfoxides via an intermolecular Pummerer rearrangement. This methodology displays an excellent functional group tolerance, furnishing 50 diverse thiazole scaffolds derived from both thioamides and thioureas. The synthetic and medicinal impact of this methodology is showcased in the preparation and evaluation of thioether, sulfoxide and sulfone analogues of the blockbuster β3-adrenoceptor agonist mirabegron. Comparison of key pharmacokinetic properties revealed improved cell permeability, metabolic stability, lipophilicity and plasma protein binding without unduly affecting biological affinity relative to the parent drug.