Nickel‐Catalyzed Ortho C–H Methylation of Aromatic Amides with Di‐tert‐butyl Peroxide as Methylation Reagent

Abstract

A new efficient protocol for the ortho‐methylation of benzamides with DTBP has been developed via Ni(II)‐catalyzed C–H activation directed by 8‐aminoquinoline. This method is performed under base‐free, ligand‐free conditions and utilizes cheap and commercially available reagents. Moreover, the by‐product acetone derived from DTBP does not affect the purification of the product.

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

“…Conveniently, the methodology did not require the use of an external base or ligand, nor demanded moisture-free or inert atmospheric conditions (Scheme 25D). 87 Additionally, the use of DTBP afforded acetone View Article Online as a by-product, aiding the isolation of the methylated product.…”

Electro‐oxidative Methylation of 2‐Isocyanobiaryls Using N,N‐dimethylformamide (DMF) as Carbon Source: Synthesis of 6‐Methylphenanthridines

“…An incorporation of a simple methyl moiety can profoundly influence several critical parameters such as drug‐bioreceptor interactions, bioavailability, solubility, and metabolism [1] . Consequently, a multitude of both indirect and direct methylation procedures have been developed, utilizing a diverse range of methylation agents, including dimethyl sulfoxide (DMSO), [2] N , N ‐dimethylformamide (DMF), [3a–b] N , N ‐dimethylacetamide (DMA), [3c] acetic acid, [4] trimethylaluminum, [5] tert ‐butyl hydroperoxide, [6] tetramethyltin, [7] iodomethane, [8] methylboronic acid, [9] and diazomethane [10] …”

Activation of DMSO(-d6) via heterogeneous photo-Fenton-like process with in situ production of hydroxyl radicals for the C–H (trideutero)methylation of (iso)quinoliniums

“…Recently, the addition of a methyl (–CH 3 ) group to small organic molecules has gained recognition in medicinal chemistry and the pharmaceutical industry due to its potential to modulate and enhance the drug-bioreceptor interaction, bioavailability, solubility, and metabolism, giving rise to the “magic methyl effect”. 1 Consequently, several indirect- and direct methylation protocols have been developed using a variety of methylation reagents, including iodomethane, 2 tert -butyl hydroperoxide, 3 tetramethyltin, 4 diazomethane, 5 dicumyl peroxide, 6 methylboronic acid, 7 potassium methyltrifluoroborate, 8 methylmagnesium chloride, 9 dimethyl sulfoxide (DMSO), 10 acetic acid, 11 and trimethylaluminium. 12 Compared to other methylation reagents, DMSO activation and the generation of the methyl-radical (˙CH 3 ) in situ for the rapid construction of methylated (hetero)arenes have attracted significant interest (Scheme 1) 13 because DMSO is non-toxic, widely available, and works with the action of the conventional Fenton reagent (H 2 O 2 and Fe 2+ /Fe 3+ , Scheme 1a).…”