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

Abstract

While remarkable progress has recently been made for the direct C−H‐functionalization of azines, its application is still limited by a lack of accessible functional groups (primarily carbon‐based) and poor regioselectivity. In contrast, C2‐functionalized pyridines and quinolines can be easily synthesized by treating readily available N‐oxides with various reagents under appropriate activation conditions. This review seeks to comprehensively document the available synthetic methods for introducing functional groups at the C2 position of pyridines and quinolines. In this work, we highlight recent developments in the C2‐functionalization of pyridine and quinoline N‐oxides and address both the mechanisms and regioselectivity of the reactions. We also describe the pathways and reactive species involved in these processes and highlight a number of medically relevant nitrogen heteroaromatics.

Recent Applications of Quinolinium Salts in the Synthesis of Annulated Heterocycles

“…34 Wang's group summarized recent strategies towards C-2 functionalized pyridines and quinolines using N-oxide chemistry. 35 However, in the recent years, a number of novel synthetic methodologies have been emerged exploiting various quinolinium salts to build diverse molecular frameworks. Therefore, a new direction on this area seems to be appropriate.…”

Electrochemical ammonium-cation-assisted pyridylation of inert N-heterocycles via dual-proton-coupled electron transfer

“…Pyridines are among the most representative heterocycles in pharmaceuticals, materials, natural product molecules, and organic functional materials ( Yadav and Reddy, 2003 , Chen et al, 2006 ; Moser et al., 2008 ; Misale et al., 2012 ; Afeli et al., 2013 ; Felding et al., 2014 ; Kouznetsov et al., 2017 ; Gil-Martins et al., 2020 ). As a result, new methods for the construction of functionalized pyridines from abundant precursors are an important synthetic goal ( Nakao, 2011 ; Murakami et al., 2017 ; Wang et al., 2021 , Zhou and Jiao, 2021 ). It is considered a straightforward and challenging protocol to access biologically active N-heterocyclic compounds from the inert N-heterocycles with cyanopyridine derivatives via the mechanism of radical cross-coupling reaction ( Scheme 1 A) ( Proctor and Phipps, 2019 ; Bordi and Starr, 2017 ; Dong et al., 2021 , Jin and MacMillan, 2015 ; Li, 2009 ; Ma et al., 2017 , Wang et al., 2017 ).…”

“…In recent years, multifarious important pyridine-containing functional molecules have been constructed based on the decyanation of cyanopyridines mediated by electrochemical reduction ( Xu et al., 2021 ; Zhang et al., 2020 , 2021 ; Lehnherr et al., 2020 ; Wen et al., 2021 ). Previously, we have delivered the C3 pyridylation of quinoxalin-2(1H)-ones with readily available cyanopyridines under the electrochemical conditions by employing HFIP as the protonation reagent ( Scheme 1 C) ( Wen et al., 2021 ).…”

Recent Advances in Transition-Metal-Free Late-Stage C-H and N-H Arylation of Heteroarenes Using Diaryliodonium Salts

“…The arylation was found to be tolerant of various substituted substrates in moderate to good yields depending on the heteroarene. This late-stage C-2 arylation of these essential pharmacophores provided a practical strategy for the synthesis of attractive N -heterobiaryl derivatives that are widely found in pharmaceuticals and natural compounds, particularly in alkaloids [ 77 , 78 , 79 , 80 , 81 ].…”