Metal‐free Deoxygenative 2‐Amidation of Quinoline N‐oxides with Nitriles via a Radical Activation Pathway

Abstract

A metal-, base-and reductant-free approach for the efficient synthesis of various Nacylated 2-aminoquinolines was reported. In this work, readily available nitriles are used as the amide source, and methyl carbazate as both the radical activating reagent and oxygen source. This is the first report on the ester-radical-activated highly regioselective addition of nitriles to quinolone N-oxides. This procedure is expected to complement the current methods for functionalization of N-oxides via an electrophilic activation mechanism.

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

“…[46] Notably, He's group reported another efficient protocol operating through a radical activation pathway, with nitriles used as the amide source and methyl carbazate as both the radical activating reagent and oxygen source (Scheme 25). [47] First, methyl carbazate was oxidized by Selectfluor to generate a carboncentered ester radical with the release of molecular nitrogen, HF, and tetrafluoroborate. The ester radical reacted with 19 to produce a radical intermediate, 87, which was further oxidized to give a quinolinium intermediate, 88.…”

Recent Progress in Non‐Catalytic C–H Functionalization of Heterocyclic N‐Oxides

“…In this case, the methyl carbazate was used as a radical activator and oxygen source in the presence of selectfluor. [ 42 ]…”

“…[41] Several approaches for deoxygenative amidation of quinoline N-oxides with nitriles were developed (Scheme 23). [42][43][44] One of them is based on the activation of nitriles by an acid catalyst providing active nitrilium cations. [43,44] Therefore, the reaction mechanism appears to be similarly shown in Scheme 21 where secondary amides are dehydrated into the nitrilium cations.…”

“…In this case, the methyl carbazate was used as a radical activator and oxygen source in the presence of selectfluor. [42] Despite these methodologies provide a wide range of highly diversified N-acylated 2-aminoquinolines using alkyl and aryl nitriles, harsh reaction conditions, and a large excess of nitriles are needed.…”

Regioselective Cyanation of Six‐Membered N‐Heteroaromatic Compounds Under Metal‐, Activator‐, Base‐ and Solvent‐Free Conditions

“…Therefore, it is apparent that these particular methodologies need not only high cost but have environmental issues. However, the greatest and most obvious drawback in most of these cases is the lack of regioselectivity…”