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Issue 25, 2018
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Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

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Abstract

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug pKa, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp3)–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 N-fluorobenzenesulfonimide. We also report heterobenzylic trifluoromethylthiolation and 18F-fluorination, providing a suite of reactions for late-stage C(sp3)–H functionalization of drug leads and radiotracer discovery.

Graphical abstract: Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

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Supplementary files

Article information


Submitted
15 Mar 2018
Accepted
25 May 2018
First published
07 Jun 2018

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2018,9, 5608-5613
Article type
Edge Article

Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

M. Meanwell, B. S. Adluri, Z. Yuan, J. Newton, P. Prevost, M. B. Nodwell, Chadron M. Friesen, P. Schaffer, R. E. Martin and R. Britton, Chem. Sci., 2018, 9, 5608
DOI: 10.1039/C8SC01221K

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