Scalable Synthesis of Cinnamylamines Via the Heck Reaction: Application in the Synthesis of Abamine, Naftifine and Reboxetine

Abstract

AbstractFollowing an extensive screening of reaction parameters such as the nature and amount of bases, Pd pre‐catalysts, ligands, additives, solvents and temperature range, we succeeded in developing a Heck reaction using N‐Boc‐allylamine and commercially available aryl bromides, capable of delivering a wide range of Boc‐protected trans‐cinnamylamines with 75–85 % regio‐ and stereoselectivity over other isomers. Optimisation of the Boc‐deprotection step and its work‐up procedure allowed for all minor isomers and impurities to be purged thus isolating pure trans‐cinnamylamines typically in 55–65 % yield without need for chromatography. We have successfully performed this chemistry in up to 5 g scale and demonstrated its usefulness by applying it to the synthesis of abamine, naftifine hydrochloride and a formal synthesis reboxetine mesylate.