Sonogashira Cross‐Coupling Reaction of Bromocyanofluoro Pyridine Compounds: Access to 5‐ and 6‐Alkynylfluoropyridinamidoximes Scaffolds

Abstract

We disclose a general two‐step procedure to access hitherto unknown and under explored 5‐ and 6‐alkynyl‐3‐fluoro‐2‐pyridinamidoximes from 5‐ and 6‐bromo‐3‐fluoro‐2‐cyanopyridines and a wide range of easily available and bench‐stable terminal alkynes, using Sonogashira cross‐coupling, as the first step. The generation of the polar amidoxime group is realized at a late stage upon treatment of the alkynylfluorocyanopyridine by hydroxylamine. This mild and operationally simple two‐step room temperature process is compatible with enantiopure chiral substrates and various functionality including free alcohols, unprotected and CBz‐protected amines, acetonides, benzyl ethers, amide, imide, di‐substituted alkynes and strained saturated heterocycles.

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes†

“…Simple Sonogashira coupling. The Pd/CuI/PPh 3 catalyst system together with amines was often applied in Sonogashira coupling of aryl bromides, iodides [15] and arylsulfonium salts. [16] Later, Pd/CuI/PEPPSI catalyst system was developed for the Sonogashira coupling.…”

Straightforward Synthesis of Halopyridine Aldehydes via Diaminomethylation

“…Fluoropyridines are versatile components in pharmaceuticals, serving as both pharmacophore cores and modifying groups. Their presence allows for the design and optimization of pharmaceutical compounds with desired therapeutic effects and improved drug properties [1–3] . Fluoro‐substituted pyridine structures can be found in approved drugs such as enoxacin, tosufloxacin, and other fluoroquinolone antibiotics [4] .…”

“…Their presence allows for the design and optimization of pharmaceutical compounds with desired therapeutic effects and improved drug properties. [1][2][3] Fluorosubstituted pyridine structures can be found in approved drugs such as enoxacin, tosufloxacin, and other fluoroquinolone antibiotics. [4] Fluorine atoms alter biological activity and provide distinctive physicochemical properties.…”