Selective Methylation of Amides, N-Heterocycles, Thiols, and Alcohols with Tetramethylammonium Fluoride

Abstract

We herein disclose the use of tetramethylammonium fluoride (TMAF) as a direct and selective methylating agent of a variety of amides, indoles, pyrroles, imidazoles, alcohols, and thiols. The method is characterized by operational simplicity, wide scope, and ease of purification. Our computational studies suggest a concerted methylation−deprotonation as the preferred reaction pathway.

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

“…indoles, pyrroles, and imidazoles) alcohols, thiols, and sulfonamides in a highly efficient manner and often with remarkable site-selectivities (e.g. methylation of amides, indoles, and alcohols in the presence of anilines and primary alkyl amines) [179]. Moreover, Schoenebeck and co-workers proved in that work that TMAF possesses an unprecedented dual role acting as a base and a methyl source in a concerted manner.…”

“…Remarkably, this method was also competent to render the chemoselective methylation of some N-based heterocycles with widespread applicability in the medicinal chemistry arena (e.g. indoles, pyrroles, imidazoles) [179]. In that field, the methylation of protic functional groups is a pivotal strategy to tune the physicochemical, conformational, and protein-binding properties of therapeutically relevant molecules.…”

“…However, toluene was deemed as the solvent of choice due to the fact that the main byproduct of the reaction-Me 3 NHF-precipitates in toluene at room temperature, which facilitates straightforward purification of the crude reaction mixture by filtration through a small pad of silica. Model system for reaction development [179], (c) Synthetic scope [179], (d) Chemoselectivity experiments [179] and (e) Mechanistic DFT studies [179]).…”

“…Scheme 22. Schoenebeck's chemoselective methylation[182]: (a) Mechanistic observation[181], (b) Model system for reaction development[179], (c) Synthetic scope[179], (d) Chemoselectivity experiments[179] and (e) Mechanistic DFT studies[179]). …”

Additive-free selective methylation of amines with formic acid over a Pd/In2O3 catalyst

“…1 Methylation of an amine in a drug molecule can have a strong effect on its lipophilicity and potency. 2 For these reasons, the development of methylation methods continues to attract the interest of chemists. The most common methods for synthesizing methylamines involve stoichiometric quantities of highly toxic methylating agents such as methyl iodide, formaldehyde, diazomethane or dimethylsulfate and generate abundant waste.…”