Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives†,Chemical Science

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Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives†
Chemical Science ( IF 7.6 ) Pub Date : 2018-06-07 00:00:00 , DOI: 10.1039/c8sc01221k
Michael Meanwell ₁ , Bharani Shashank Adluri ₁ , Zheliang Yuan _{1,

2} , Josiah Newton _{1,

3} , Philippe Prevost ₁ , Matthew B Nodwell ₁ , Chadron M Friesen ₃ , Paul Schaffer ₂ , Rainer E Martin ₄ , Robert Britton ₁

Affiliation

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug pK_a, 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.

中文翻译：

使用二苯磺酰胺衍生物进行直接杂苄基氟化、二氟化和三氟甲硫基化†

具有单氟烷基或二氟烷基的杂环支架的功能化提供了调节药物pKa _、影响效力和膜通透性以及减弱代谢的独特机会。虽然在杂环上添加氟代烷基方面已经取得了进展，但直接的 C(sp ³ )–H 杂苄基氟化相对而言尚未被探索。在这里，我们展示了使用依赖于亲电氟化剂N-氟苯磺酰亚胺瞬时磺酰化的便捷方法对一系列烷基杂环进行单氟化和二氟化。我们还报道了杂苄基三氟甲硫基化和¹⁸ F-氟化，为药物先导物的后期 C(sp ³ )–H 功能化和放射性示踪剂的发现提供了一系列反应。

更新日期：2018-06-07

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