Phosphonium-Salt-Catalyzed N-Methylation and N-Formylation of Amines with CO₂

The use of CO2 as a C1 building block is of great relevance and is a focus of current research. Herein we report the synthesis of air-stable internal phosphonium salts and their application as catalysts in the N-methylation and N-formylation of amines utilizing CO2. A series of catalysts were prepared and tested for these valuable transformations. Under the optimized reaction condition, the N-formylation of amines was achieved at 23 °C, 1 bar CO2 pressure under solvent-free conditions using equimolar amounts of n-hexylsilane as reducing agent. A modification of the reaction conditions led to a selectivity switch, and the N-methylation was realized at 70 °C in acetonitrile using the same catalyst and reductant. In total, 22 amines were converted to the corresponding N-methylated products in up to 99% yield. Moreover, 25 examples of the conversion to the corresponding N-formylated products in up to 96% yield are reported. Both reactions can be performed at large scale. Both the N-methylation and N-formylation reactions were also applied to the late-stage functionalization of the pharmaceutical sertraline. NMR studies and control experiments revealed two different reaction pathways and intermediates for N-methylation and N-formylation.