Direct Access to Classic Psychedelic Phenethylamines Via an Optimized Suzuki Coupling

2,5-Dimethoxyphenethylamines represent a prominent scaffold among psychedelic phenethylamines and are currently being extensively investigated due to their ability to activate serotonin 5-HT_2A receptors, a mechanism that may contribute to their therapeutic potential across a broad range of neuropsychiatric disorders. Traditionally, the preparation of these derivatives involves a Henry reaction followed by an exhaustive reduction.¹ In this work, we report the optimization of a novel methodology that enables the direct synthesis of 2,5-dimethoxyphenethylamines. This approach features a Suzuki cross-coupling reaction between a potassium β-aminoethyltrifluoroborate and an aryl bromide as the key synthetic step.² Temperature, palladium source, ligand and base were evaluated leading to optimal conditions for the procedure. Ultimately, this streamlined methodology significantly simplifies the preparation of these classic psychedelics, reducing purification steps while improving overall yields.