Selective Methylation of Arenes: A Radical C−H Functionalization/Cross‐Coupling Sequence

Abstract

A selective, nonchelation-assisted methylation of arenes has been developed. The overall transformation, which combines a C-H functionalization reaction with a nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late-stage methylation of small-molecule pharmaceuticals.

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

“…This principle has been impressively harnessed by Ritter, demonstrating charge-transfer directed radical aromatic substitution as a means of para-selective C-H functionalisation (Scheme 61C). 17j, 163 The highly electrophilic [triethylenediamine] 2+ (TEDA 2+ ) aminium radical generated from Selectfluor-II, was found to forge C-N bonds selectively at the para-position of numerous complex carboarenes and biologically active substrates with near-absolute selectivity. Arene-to-radical charge transfer in the transition state for radical addition was postulated as the primary reason for high positional selectivity, with substitution occurring at the site from which charge transfer is the greatest.…”

Bioinspired design of a robust d 3 -methylating agent

“…All new compounds were fully characterized. 1 H, 13 C, and 19 F nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III 400 or 500 MHz spectrometer. 1 Infrared spectra were recorded on a Fourier transform infrared spectrometer.…”

“…Inspiration by SAM, Baran and coworkers (8) developed an elegant methylating agent, zinc bis(phenylsulfonylmethanesulfinate), for the methylation of heteroarenes. Very recently, other methylating reagents such as 1,1-diborylmethane (9), -iodosulfones (10), trimethylphosphate (11), 1-methoxy-2,2,6,6-tetramethylpiperidine (TEMPO-Me) (12), MeZnCl (13), Lewis base BH 3 /DMF (14), and [Me 2 Cl][Al(OTeF 5 ) 4 ] (15) exhibit unique reactivity during the research of methylation. Despite these notable advances, the corresponding d 3 -methylation has not been well developed.…”

Palladium-Catalyzed Methylation of Aryl, Heteroaryl, and Vinyl Boronate Esters

“…A protocol developed by Minisci and co-workers for methylation of electron-deficient hetereoarenes with methyl radicals leads to reaction at the electron-poor positions . Minisci-type C–H functionalizations conducted with photoredox catalysts and peroxo sources or methanol to form methylated heteroarenes have been reported recently with similar regioselectivity.…”