C2-Selective C–H Methylation of Heterocyclic N-Oxides with Sulfonium Ylides

Abstract

A redox-neutral C2-selective methylation of heterocyclic N-oxides with sulfonium ylides is described herein. This report presents unprecedented findings for the utility of sulfonium ylides as the methylation source of N-heterocycles beyond the Corey–Chaykovsky reaction. Intriguingly, pyrrolidine plays a significant role in minimizing the reductive C2-methylation process. This method is characterized by its mild conditions, simplicity, and excellent site selectivity. The applicability of the developed protocol is showcased by the late-stage methylation and sequential transformations of complex drug molecules.

Alkylation of Nitropyridines via Vicarious Nucleophilic Substitution

“…In turn, Kim and co-workers demonstrated alkylation of quinoline N -oxides and pyrazinones with sulfonium and sulfoxonium salts at elevated temperatures. 15 Interestingly, our own exploration of related Corey–Chaykovsky reagents (in which EWG = LG), such as alkyl phenyl selenones and alkyldiphenyl sulfonium salts, revealed different reactivity in which intermediate adducts spontaneously cyclized (γ-eliminated) to cyclopropanes, giving dearomatized benzonorcaradienes ( Scheme 1 , bottom). 16 We reckoned that precursors with worse leaving group ability, such as alkyl sulfones and sulfonates, may suppress the cyclization but still undergo base-induced β-elimination to give alkylated products.…”

Site-selective and metal-free C–H nitration of biologically relevant N-heterocycles

“…Despite the compelling progress on the C–H nitration reaction of various N -heterocycles, the site-selective nitration reaction of quinoxalinones and pyrazinones under milder reaction conditions is still unexplored. Driven by our ongoing interest in the C−H functionalization of N -heterocycles (Han et al 2018 ; Ghosh et al 2019 , 2021 ; An et al 2020 ; Park et al 2021 ), we herein describe the metal-free and site-selective C–H nitration reaction of quinoxalinones and pyrazinones with tert -butyl nitrite as a readily available nitrating agent. Notably, the gram-scale reaction, selective reduction of a nitro group, and thiocarbonylation demonstrate the synthetic utility of the developed method.…”

Transition Metal Free α−C−H Functionalization of Six Membered Heteroaromatic‐N‐Oxides

“…Treatment of quinoline N-oxides 18 with benzyltrimethylsilane in the presence of catalytic amount of tetrabutylammonium fluoride and triethylsilane as an additive produced the 2-benzylated quinolines 134 in good to excellent yields (Scheme 51). [71] Notably, quinoline N-oxide having electron withdrawing functional groups did not afford the required products under the above mention reaction conditions. Benzyltrimethylsilane containing electron-donating or electron withdrawing substituents underwent cross-coupling reaction to deliver the product in good yield.…”