Charting the Chemical Reactivity Space of 2,3-Substituted Furo[2,3-b]pyridines Synthesized via the Heterocyclization of Pyridine-N-oxide Derivatives

Abstract

A concise strategy for the synthesis of 2,3-substituted furo[2,3-b]pyridines is described. Mild, metal-free conditions were successfully applied to produce a range of 2-(alkyl or aryl)-3-ethylcarboxylate-furo[2,3-b]pyridines in yields of 50-91%. Then, the chemical reactivity of this heterocyclic framework was explored to develop straightforward methods for its functionalization. The pyridine moiety reactivity was successfully explored by C-H amination and borylation reactions, although C-H fluorination and radical C-H arylation processes were not as efficient. In addition, while the furopyridine core proved stable under basic conditions, the ring-opening reaction of the furan moiety with hydrazine generated a valuable new pyridine-dihydropyrazolone scaffold.

Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases

“…Recently our group reported a concise strategy to synthesize and decorate this core through C−H activation reaction [23] . The synthesis of furo[2,3‐ b ]pyridines started from pyridine‐ N‐ oxide derivative ( IV ) [23] . Under mild, metal‐free conditions, we synthesized the furopyridines derivatives 41 – 44 with appropriated acyl chlorides ( V ).…”

“…[23] The synthesis of furo [2,3-b]pyridines started from pyridine-N-oxide derivative (IV). [23] Under mild, metal-free conditions, we synthesized the furopyridines derivatives 41-44 with appropriated acyl chlorides (V). In addition, we functionalized this heteroaromatic core through CÀ H amination (VI, compounds 45-53).…”

Facile and Efficient Synthesis of Tri‐ and Tetrasubstituted 7‐Azabenzofuran Derivatives

“…Both the key step of this synthesis and the whole synthetic sequence have been optimized. Especially, the method originally developed by Emery is not suitable for complex pyridine N ‐oxide substrates and requires the use of a large excess of DMAP to synthesize the 7‐azabenzofuran core, while the new method we developed is much better and does not need any DMAP. Furthermore, several synthetic drawbacks have been overcome.…”

Recent Advances in the Synthesis of C2‐Functionalized Pyridines and Quinolines Using N‐Oxide Chemistry

“…[132] Emery's team reported a method for the metal-free synthesis of furo [2,3-b]pyridines 336 (also known as 7-azabenzofuran) at ambient temperatures (Scheme 100). [133] 3-Ethylcarboxylate pyridine N-oxides 335 react with acyl chloride or anhydride to form ethyl acetoacetate derivatives 337, which undergo carbonyl deprotonation and cyclization to generate 338. Finally, deprotonation and rearomatization provide the target products, 336.…”