Mechanochemical Solvent‐Free Catalytic C−H Methylation

Abstract

The mechanochemical, solvent‐free, highly regioselective, rhodium‐catalyzed C−H methylation of (hetero)arenes is reported. The reaction shows excellent functional‐group compatibility and is demonstrated to work for the late‐stage C−H methylation of biologically active compounds. The method requires no external heating and benefits from considerably shorter reaction times than previous solution‐based C−H methylation protocols. Additionally, the mechanochemical approach is shown to enable the efficient synthesis of organometallic complexes that are difficult to generate conventionally.

Rhodium(III)-Catalyzed C–H Activation in Indole: A Comprehensive Report (2017–2022)

“…1-(Pyrimidin-2-yl)-1 H -indoles were treated with MeB(OH) 2 as the methyl source in the presence of [Cp*RhCl 2 ] 2 as the catalyst and Ag 2 CO 3 as an oxidant in a stainless steel (SS) milling vessel equipped with a single SS ball using a mixer mill (MM) with the ability to oscillate at frequencies up to 36 Hz and gave 2-methyl-1-(pyrimidin-2-yl)-1 H -indoles in 72–99% yields (Scheme 33 ). 74 This process proceeds through a five-membered rhodacycle. This mechanochemical process involves shorter reaction times, no solvent, and no external heating.…”

“…Indoline was activated at both C2–H and C7–H by the varying frequency of the mixer mill (MM) (Scheme 34 ). 74 Reaction of 1-(pyrimidin-2-yl)indoline with MeBF 3 K, [Cp*RhCl 2 ] 2 , AgSbF 6 , and Ag 2 CO 3 at 25 Hz resulted in 7-methyl-1-(pyrimidin-2-yl)indoline with no dimethylation, while reaction at 36 Hz gave 2,7-dimethyl-1-(pyrimidin-2-yl)-1 H -indole. Control experiments showed that both Ag 2 CO 3 and Me-BF 3 K are necessary to form 2,7-dimethyl-1-(pyrimidin-2-yl)-1 H -indole.…”

Mechanochemical Asymmetric Transfer Hydrogenation of Diketones to Access Chiral 1,3-Diols under Solvent-Free Conditions

“…11 The Pilarski group developed a highly regioselective mechanochemical C–H methylation of (het)arenes in the presence of a rhodium complex under solvent-free conditions. 12 This protocol requires shorter reaction times than with previous solution-based reactions, and no external heating is necessary. The Geneste group realized a hydroxylation of aryl or hetaryl fluorides by using KOH as base with the assistance of ball milling.…”

Exploration of C‐H Activation Strategies in Construction of Functionalized 2‐Aryl Benzoazoles: A Decisive Review

“…This introduces a solvent free, lower operating temperatures and reduced reaction time strategy to afford desired protocol and also opens new mechanistic pathways to study. [42c,d] Recently in 2021, Pilarski and co‐workers [42e] successfully accomplished a Rh‐catalyzed methylation 40 of 2‐phenyl benzothiazole with methyltrifluroborate 39 a as methylating agent. Authors also enumerated the concept to other directing groups such as phenyl‐pyridine, indoline etc.…”