Trideuteromethylation Enabled by a Sulfoxonium Metathesis Reaction

Abstract

A conceptually novel sulfoxonium metathesis reaction between TMSOI and cost-effective DMSO-d 6 is developed for the efficient generation of a new trideuteromethylation reagent TDMSOI. The new reagent TDMSOI is produced highly efficiently by simply heating a mixture of TMSOI and DMSO-d 6 and directly used for subsequent trideuteromethylation in a “one-pot” operation. The preparative power of the new versatile reagent and the “one-pot” protocol is demonstrated by its use to install the −CD3 moiety into broad functionalities including phenols, thiophenols, acidic amines, and enolizable methylene units in high yield and at a useful level of deuteration (>87% D).

Methylthiolation for Electron‐Rich Heteroarenes with DMSO‐TsCl

“…(entries [13][14][15]. To further improve the yield, several bases were also examined and Et 3 N was found to give the best result (entries [16][17][18]. The investigation of the effect of reaction temperature revealed that 70°C was the optimal temperature (entries [19][20][21].…”

“…Dimethyl sulfoxide (DMSO) is a readily available and less toxic polar solvent [15] . During the past decades, it was reported as important precursors for many organic motifs such as −CH 3 , [16] −CHO, [17] −CN, [18] −SMe, [19] −SOMe, [20] and −SO 2 Me [21] . Cheng's group reported a Cu(I)‐mediated methylthiolation of aryl iodides and aryl bromides with DMSO using ZnF 2 at 150 °C (Scheme 1b) [22] .…”

Trialkylammonium salt degradation: implications for methylation and cross-coupling

“…This solvent also links to earlier NMR kinetics investigations involving methyl iodide 56 and DMSOmediated methylation studies. 57,58 Importantly, detailed studies applying solvents applicable to a broader range of methylation and catalytic chemistries is also included (see Experimental ESI Sections 20 and 22 †). A graph showing the extent of degradation of each salt aer a 20 min period is shown in Fig.…”

Frontispiece: The Deuterated “Magic Methyl” Group: A Guide to Site‐Selective Trideuteromethyl Incorporation and Labeling by Using CD3 Reagents

“…Very recently, a new trideuteromethylation reagent was developed by a metathesis reaction between [D 6 ]DMSO and trimethylsulfoxonium iodide (TMSOI). [86] This reagent can become a cheap and nontoxic alternative for CD 3 I. The reagent was used as electrophilic CD 3 -reagent (Scheme 21).…”