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.

Site-Selective C–H alkylation of Complex Arenes by a Two-Step Aryl Thianthrenation-Reductive Alkylation Sequence

“…The reaction is thought to proceed via the in situ formation of an alkylzinc species. Compared to many other related Negishi-type aryl alkylations, thianthrene-based reductive couplings do not require the organometallic zinc to be preformed prior to the cross-coupling event. ,, The ability to engage structurally complex arenes at a late stage, a broad selection of alkyl iodides, and excellent functional group tolerance distinguish this protocol to quickly access new value-added chemical entities.…”

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 H NMR spectra data were reported as  values in parts per million relative to CDCl 3 ( = 7.26), CD 3 CN ( = 1.94), CD 3 OD ( = 3.31), or DMSO-d 6 ( = 2.50).…”

“…1 H NMR spectra data were reported as  values in parts per million relative to CDCl 3 ( = 7.26), CD 3 CN ( = 1.94), CD 3 OD ( = 3.31), or DMSO-d 6 ( = 2.50). 13 C NMR spectra data were reported as  values in parts per million relative to CDCl 3 ( = 77.00), CD 3 CN ( = 118.30), CD 3 OD ( = 49.15), or DMSO-d 6 ( = 39.52). Mass spectra were conducted at Micromass Q-Tof instrument electron spray ionization (ESI) and Agilent Technologies 5973N electron ionization 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.…”

Cobalt-Catalyzed Alkylation of Drug-Like Molecules and Pharmaceuticals Using Heterocyclic Phosphonium Salts

“…Methylation of azines is a common strategy in drug development, and we tested MeZnCl in this coupling process. 15,16 While less efficient than n -BuZnCl as a coupling reagent, four examples of pyridines and quinolines were alkylated in reasonable yields ( 2ag–2aj ). 17…”