Iron-Catalyzed N-Alkylation of Secondary Amines with Alcohols Using Borrowing Hydrogen Strategy

Iron-based catalysts have been widely used in N-alkylation of amines with alcohol using borrowing hydrogen strategy, due to low toxicity and cost. Herein, based on Saito and co-workers' experiment, we discuss a possible mechanism for N-alkylation of secondary amines with alcohol under an iron-based catalyst using DFT calculations. Contrary to N-alkylation of primary amines, only one hydrogen on alcohol benzyl group is taken by the iron-catalyst during radical transfer process. Thus, instead of forming an imine, a structure with a radical is formed. Overall, there are three parts to this mechanism: 1) hydrogen borrowing by the iron-based catalyst; 2) radical addition; 3) hydrogen reduction. There are two possible pathways of hydrogen borrowing: either by a distal oxygen or by the oxygen directly coordinating with iron. According to the computed free energy barrier, the former one is more favorable. We also found four possible pathways of radical addition. Our calculations suggest a direct dehydration step with short steps and lower energy barrier was more favorable.