Robust and Scalable Reductive Amination Protocol for Electron-Poor Heterocyclic Amines Using Et3SiH/TFA as Reducing Agent

Abstract A facile reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes has been developed. The key to success was the use of triethylsilane (Et3SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH2Cl2. The reductive aminations are fast and clean, and allow for the isolation of the alkylated amines in high yields and purity after crystallization or chromatographic purification. The robustness and scalability of the process has been demonstrated for one substrate combination on 750 g scale, leading to the isolation of the corresponding product in 93% yield.