Reductive C2‐Alkylation of Pyridine and Quinoline N‐Oxides Using Wittig Reagents

Abstract

The ability to alkylate pyridines and quinolines is important for their further development as pharmaceuticals and agrochemicals, and for other purposes. Herein we describe the unprecedented reductive alkylation of pyridine and quinoline N-oxides using Wittig reagents. A wide range of pyridine and quinoline N-oxides were converted into C2-alkylated pyridines and quinolines with excellent site selectivity and functional-group compatibility. Sequential C-H functionalization reactions of pyridine and quinoline N-oxides highlight the utility of the developed method. Detailed labeling experiments were performed to elucidate the mechanism of this process.

Beyond Friedel and Crafts: Innate Alkylation of C−H Bonds in Arenes

“…Finally, Han and Kim elegantly exploited Wittig reagents to promote the direct C2‐alkylation of pyridine and quinoline N ‐oxides to furnish the corresponding C2‐alkylated pyridines and quinolines in good yields (Scheme ) . This transformation is particularly attractive for the introduction of methyl and primary alkyl groups, while secondary alkyl groups have been far less investigated (two examples).…”

“…Other reagents have indeed been exploited for the selective alkylation of C−H bonds in electron‐deficient heteroarenes: they include alcohols, carboxylic acids, peroxides, aldehydes, acyl chlorides, as well as some less common reagents such as pyridinium salts, dihydropyridines, N ‐tosylhydrazones, N ‐(acyloxy)phthalimides, α‐diazocarbonyl derivatives, α‐carbonyl alkylsulfones, carboxylic xanthates, cycloalkanols, and Wittig reagents …”

Jenseits von Friedel und Crafts: immanente Alkylierung von C‐H‐Bindungen in Arenen

“…Auch andere Reagenzien wurden für die selektive Alkylierung von C‐H‐Bindungen in elektronenarmen Heteroarenen genutzt: Hierzu zählen Alkohole, Carbonsäuren, Peroxide, Aldehyde, Acylchloride sowie einige weniger gebräuchliche Reagenzien wie Pyridiniumsalze, Dihydropyridine, N ‐Tosylhydrazone, N ‐(Acyloxy)phthalimide, α‐Diazocarbonylderivate, α‐Carbonylalkylsulfone, Xanthogenate, Cycloalkanole und Wittig‐Reagenzien …”

“…Schließlich nutzten Han und Kim auf elegante Weise Wittig‐Reagenzien zur Förderung der direkten C2‐Alkylierung von Pyridin‐ und Chinolin‐ N ‐oxiden unter Bildung der entsprechenden C2‐alkylierten Pyridine und Chinoline in guten Ausbeuten (Schema ) . Diese Transformation ist besonders attraktiv für die Einführung von Methyl‐ und primären Alkylgruppen, während sekundäre Alkylgruppen deutlich weniger ausführlich untersucht wurden (zwei Beispiele).…”

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

“…[1] However, the therapeutic effect of the N-heterocyclic scaffolds (such as the quinoline moiety) is often detoxified in the body due to the hydroxylation at the C-2 position, thereby resulting in the decline of the aforementioned therapeutic effect. [3] Among them, functionalization with a nitrile group is an important methodology as it plays a key role in chemistry, biology, and medicine. [3] Among them, functionalization with a nitrile group is an important methodology as it plays a key role in chemistry, biology, and medicine.…”