C3 Selective Chalcogenation and Fluorination of Pyridine Using Classic Zincke Imine Intermediates

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Aug 28

PMID 39198410

Authors

Shun Li

Juan Tang

Yonglin Shi

Meixin Yan

Yihua Fu

Zhishan Su

Jiaqi Xu

Weichao Xue

Xueli Zheng

Yicen Ge

Ruixiang Li

Hua Chen

Haiyan Fu

Affiliations

Soon will be listed here.

Abstract

Regioselective C-H functionalization of pyridines remains a persistent challenge due to their inherent electronically deficient properties. In this report, we present a strategy for the selective pyridine C3-H thiolation, selenylation, and fluorination under mild conditions via classic N-2,4-dinitrophenyl Zincke imine intermediates. Radical inhibition and trapping experiments, as well as DFT theoretical calculations, indicated that the thiolation and selenylation proceeds through a radical addition-elimination pathway, whereas fluorination via a two-electron electrophilic substitution pathway. The pre-installed electron-deficient activating N-DNP group plays a crucial and positive role, with the additional benefit of recyclability. The practicability of this protocol was demonstrated in the gram-scale synthesis and the late-stage modification of pharmaceutically relevant pyridines.

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