Transition‐Metal‐Free Radical C−H Methylation of Quinoxalinones with TBHP

Abstract

A highly efficient and generally applicable iodine‐mediated C−H methylation of quinoxalinones by using TBHP as the methylating reagent was developed. The methodology has the advantages of a metal‐free strategy, easy to handle reagents and functional group tolerance. Tentative mechanistic studies suggest that this reaction is likely to involve a radical process.

Installing the “magic methyl” – C–H methylation in synthesis

“…110 A distinct approach from Gu & Xia used a Na 2 SO 3 /I 2 couple to act as an external oxidant, via the gradual release of I-radicals capable of triggering rearomatisation of the Minisci adduct. 111 In a 2017 report from Bao, this approach has found further application in the methylation of styrene derivatives (Scheme 37C). 112 The adoption of Fe(OTf) 3 enabled both the fragmentation of a wide range of organic peroxides and the oxidation of the benzylic radical, resulting addition of the methyl radical, to enable reformation of the alkene p-bond.…”

I2/TBHP Reagent System: A Modern Paradigm for Organic Transformations**

“…The synthetic utility of this metal‐free, C−H methylation reaction has been illustrated by the efficient synthesis of benzenoid derived and N ‐allyl, N ‐alkyl, N ‐pyridin‐2‐yl methyl, N ‐naphthlen‐2‐yl methyl substituted methyl quinoxalinones (Scheme 3). [59] Mechanism illustrated in Scheme 4 reveals the generation of tert‐butoxyl radical and hydroxyl radical via thermal decomposition of TBHP. Also thermal β ‐methyl elimination from tertbutoxyl radical would produce acetone and a methyl radical.…”

Recent Progress in Methyl-Radical-Mediated Methylation or Demethylation Reactions

“…HOAc as the solvent together with a stoichiometric excess of DCP as methylation reagent were employed in this reaction. To expand the application, Yan and Xia independently disclosed a site-specific C–H methylation of quinoxalin-2­(1 H )-ones 121 , in which a free N–H moiety or propargyl group was nicely compatible under the metal-free conditions (Scheme b) …”