Site-Selective C–H Alkylation of Diazine N-Oxides Enabled by Phosphonium Ylides

Abstract

The synthesis of alkylated diazine derivatives is important for their practical utilization as pharmaceuticals and for other purposes. Herein, we describe the metal-free siteselective C−H alkylation of diazine N-oxides using phosphonium ylides that affords a variety of alkylated diazine derivatives with broad functional group tolerance. The utility of this method is showcased by the late-stage functionalization of a commercially available drug such as varenicline. Notably, the sequential C−H alkylation of pyrazine N-oxides for the total synthesis of a pyrazine-containing natural product, paenibacillin A, highlights the importance of this method.

C−H Methylation of Iminoamido Heterocycles with Sulfur Ylides**

“…[10] For examples, our group recently described the reductive C2-alkylation of heteroaromatic Noxides using phosphonium ylides. [11] Vicarious nucleophilic substitution (VNS) using carbanions with leaving groups (e.g., Cl and PhS) at the carbanion center has been studied for the metal-free C À H methylation for nitroarenes and N-heteroaromatic compounds by Makosza. [12] In this process, the nature of the leaving group (X) provides the possibility of its elimination as HX from the intermediate s-complex (Scheme 1 B).…”

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

“…In addition to Grignard reagents, examples of “reductive alkylation” using Wittig reagents [ 74,75 ] and organoboron compounds [ 76 ] are known.…”

“…Some alternative to this approach for the C2-functionalization of quinoline N-oxides may be the use of organic superbase P4-tBu (Figure 8), which is used in catalytic amounts (Scheme 40). [73] In addition to Grignard reagents, examples of "reductive alkylation" using Wittig reagents [74,75] and organoboron compounds [76] are known.…”

“…Formation of alkylated diazine derivatives via the metal-free site-selective C-H alkylation of diazine N-oxides using phosphonium ylides affords a wide substrate scope, high site selectivity, and broad functional group tolerance (Scheme 42). [75] Scheme 42. Functionalization of azine N-oxides with Wittig reagents.…”

Sulfoxonium ylides for direct methylation of N-heterocycles in water

“…Recently, our group described the reductive C2-alkylation of heterocyclic N-oxides using phosphonium ylides (Fig. 1b) [35][36] . In this reaction, a concerted [3+2] cycloaddition between a 1,3-dipolar fragment of pyridine N-oxides and zwitterionic phosphonium ylides provides aza-oxaphospholane intermediates, which subsequently undergo aromatization to afford C2alkylated pyridines.…”