Methyl groups are ubiquitous in organic chemistry. They can bring about drastic changes in the physical and chemical properties of molecules. This effect is so pronounced in medicinal chemistry that it has been dubbed the magic methyl effect. Many common methylating reagents have significant safety or toxicity risks associated with them. Hence, safe, efficient, and practical methylating reagents are highly sought after. N,N,N-trimethylanilinium salts have been widely used as cross-coupling and SNAr substrates, but their application as methylating reagents remains underexplored (figure 1, top). A mechanistic analysis of trimethylanilinium salts is presented in this presentation. The degradation of a range of N,N,N-trimethylanilinium salts was investigated in the solid state and in solution via TGA and NMR spectroscopy, respectively, revealing the aryl substitution and counterion effects on anilinium salt stability (figure 1, bottom). Real-time 1H NMR monitoring of anilinium degradation was used to propose a degradation mechanism. Finally, the efficiency of the trimethylanilinium salts as O-methylating reagents was screened. These studies revealed that anilinium salts with more electron deficient cations and nucleophilic anions were more reactive. The findings are useful to synthetic chemists interested in applying anilinium salts in cross-coupling and methylation methodologies.

Mechanistic analysis of trimethylanilinium salts: Implications for methylation and cross-coupling chemistry

2019 Fall National Meeting

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