A tandem reduction of primary amines, carbonyl compounds, CO2, and boranes catalyzed by in situ formed frustrated Lewis pairs

2-Aminothiazole in combination with a borane-trimethylamine complex exhibits efficient catalytic activity for four-component reductive methylation of primary amines, carbonyl compounds, boranes, and CO2 (1 atm) under metal-free conditions. A wide range of highly functionalized tertiary N-methylamines are efficiently synthesized in one pot. In particular, multicomponent reductive reactions involving less reactive ketones are realized for the first time. This protocol is also applicable to the gram-scale synthesis of butenafine and late-stage modifications of several drugs. Mechanistic studies and DFT calculations indicate that an intramolecular FLP-type catalyst is generated and serves as the key for CO2 activation.

Automated summary

In this study, a four-component reductive methylation reaction catalyzed by 2-Aminothiazole in combination with a borane-trimethylamine complex was proposed. Highly functionalized tertiary N-methylamines were efficiently synthesized in one pot using this reaction. This method is not only applicable to the gram-scale synthesis of butenafine, but also suitable for late-stage modifications of several drugs.