A General and Direct Reductive Amination of Aldehydes and Ketones with Electron-Deficient Anilines

In our ongoing efforts in preparing tool compounds for investigating and controlling the biosynthesis of phenazines, we recognized the limitations of existing protocols for C–N bond formation of electron-deficient anilines when using reductive amination. After extensive optimization, we have established three robust and scalable protocols for the reductive amination of ketones with electron-deficient anilines, by using either BH₃·THF/AcOH/CH₂Cl₂ (method A), with reaction times of several hours, or the more powerful combinations BH₃·THF/TMSCl/DMF (method B) and NaBH₄/TMSCl/DMF (method C), which give full conversions for most substrates within 10 to 25 minutes. The scope and limitations of these reactions have been defined for 12 anilines and 14 ketones.