Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

• Published in: Chemical science (Cambridge) Vol. 9; no. 25; pp. 5608 - 5613
• Main Authors: Meanwell, Michael, Adluri, Bharani Shashank, Yuan, Zheliang, Newton, Josiah, Prevost, Philippe, Nodwell, Matthew B, Friesen, Chadron M, Schaffer, Paul, Martin, Rainer E, Britton, Robert
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 07-07-2018
• Subjects: Fluorination; Metabolism; Radioactive tracers
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c8sc01221k

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug p
, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp
)-H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on transient sulfonylation by the electrophilic fluorinating agent
-fluorobenzenesulfonimide. We also report heterobenzylic trifluoromethylthiolation and
F-fluorination, providing a suite of reactions for late-stage C(sp
)-H functionalization of drug leads and radiotracer discovery.