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

Abstract

Methylation is an important process in biology. To date, radical-type methylation protocols have been developed in the late-stage modifications of privileged scaffolds in pharmaceutical research and in medicinal and materials sciences. As a result, the chemistry of methyl-radical-involved conversions, which was a significant topic of interest over the past few years, has been greatly developed. This review focuses on the most recent developments in catalytic radical methylation or demethylation protocols that were mediated by methyl radicals. We classify the reactions according to the origination of the methyl radical species to illustrate the diversity of radical-based mechanisms; these radical generation pathways include (1) photo-/electro-catalysis, (2) transition-metal catalysis, (3) transition-metal-free methylations, and (4) demethylation-triggered radical cyclization/cascade reactions. In addition to the mechanisms, some of the representative methyl-containing molecules that were produced from the specific reactions are presented and analyzed.

Silyl Radical Cascade Cyclization of 2-Isocyanothioanisole toward 2-Silylbenzothiazoles through Radical Initiator–Inhibitor Symbiosis

“…With the results of these mechanistic studies and the previous reports of cyclization reactions (other than silicon, i.e., phosphorus, boron, sulfur, and carbon; Scheme b), a plausible mechanism is proposed (Scheme ). In the first step, the radical initiator di- tert -butylperoxide fragments and reacts with silane to generate the silyl radical. − Then, the silyl radical adds to the isocyano group of 1a to generate imidoyl radical-containing intermediate 8 .…”

“…In the first plausible mechanism, after cyclization, intermediate 5 is generated followed by generation of the methyl radical as a leaving group. This is a commonly accepted mechanism in a previously reported radical-triggered demethylative-cascade-cyclization reaction . Alternatively, TEMPO might assist the reaction through methyl abstraction, wherein TEMPO acquires the methyl directly from 5 and in which no free methyl radical is generated.…”

“…Traditionally, this class of structures is prepared by construction of the benzothiazole first followed by functionalization at the 2 position via a lithiation–substitution sequence in a second synthetic step (Scheme a). − Although this type of synthetic route is generally efficient, it requires the use of a organolithium reagent, which is undesirable due to its pyrophoricity and incompatibility with spectator aryl halides. Alternatively, demethylation-triggered radical cascade cyclization of 2-isocyanothioanisole derivatives toward other functionalized heterocycles has received significant attention in recent years due to its mild and metal-free reaction conditions, high atom economy, and high regioselectivity (Scheme b) . A conceptually similar radical-mediated group-transfer cyclization has also been developed with the same advantages (Scheme c). , …”

“…Alternatively, demethylation-triggered radical cascade cyclization of 2-isocyanothioanisole derivatives toward other functionalized heterocycles has received significant attention in recent years due to its mild and metal-free reaction conditions, high atom economy, and high regioselectivity (Scheme b) . A conceptually similar radical-mediated group-transfer cyclization has also been developed with the same advantages (Scheme c). , …”

Recent advances in the reactions of silacyclobutanes and their applications

“…Simultaneously, Zhao and coworkers described a general and efficient strategy for the synthesis of sila-tetralins and sila-benzosuberanes (Scheme 7). 13 The methyl group in silacyclobutane (SCBs) played a key role because of the magic methyl effect 14 in this transformation. A plausible mechanism was proposed.…”