Reductive amination is one of the most important methods to synthesize amines, having a wide application in the pharmaceutical, fine chemicals, and materials industries. In general, the reaction begins with dehydration between a carbonyl compound and an amine compound, forming an imine, which is then reduced to an alkylated amine product. Sodium triacetoxyborohydride (STAB) is a popular choice for the reducing agent as it shows selectivity for imines over aldehydes and ketones, which is particularly important in direct reductive amination where the imine and carbonyl compounds are present concurrently. Here, we analyze the reaction pathways of acid-catalyzed direct reductive amination in 1,2-dichloroethane (DCE) with acetaldehyde and methylamine. We find that the transition states for the formation and subsequent reduction of Z-methylethylideneimine (resultant aldimine from acetaldehyde and methylamine) have lower energies than the reduction of acetaldehyde. Transition state structures for the hydride transfers are organized by the Lewis-acidic sodium ion. Additionally, reduction reactions with formaldehyde and acetone and their imine derivatives (with methylamine) are investigated, and again, the hydride transfer to the resultant aldimine or ketimine is lower in energy than that of their parent carbonyl compound.
© 2022 The Authors. Published by American Chemical Society.