Challenges in the reductive amination step toward tetracaine synthesis

Tetracaine is considered the gold standard among topical local anesthetics and is widely used in ophthalmological procedures. ¹ Its clinical importance is reinforced by its inclusion in the World Health Organization's List of Essential Medicines. The reductive amination step in the reported industrial synthesis relies on toxic activating agents, pressurized reactors, and noble-metal catalysis. ^2,3 Electrochemistry has emerged as a more sustainable and cost-effective alternative for the key reductive amination between (1) and (2). Classical hydride reducing agents showed low conversion and significant by-product formation. The electrochemical reduction is based on a recently developed hydrogen atom transfer catalytic cycle promoted by ascorbic acid and 3-mercaptopropionic acid.⁴ This approach afforded trace amounts of the desired product; however, concomitant aldol condensation of butyraldehyde remains a major challenge. Further optimization aims to minimize competing reactions. Recently, photocatalytic strategies have also been evaluated and may represent a promising alternative for this transformation.