Synthesis of Tertiary Amines Using a Polystyrene (REM) Resin

A range of tertiary amines was constructed using a “traceless” linker on a polystyrene resin (REM resin), starting from secondary amines, primary amines, and resin-bound “ammonia”. The methodology is characterized by three essential steps conducted under ambient conditions:  (1) coupling of the starting amine (Michael addition) to the resin, (2) activation (quaternization), and (3) cleavage of the product amine (Hofmann elimination). The linker is compatible with both acid and base sensitive protecting group strategies. The nature of the chemistry ensures that the tertiary amine products are obtained in consistently high purity (95% or greater). After cleavage of the product, REM resin is regenerated and can be reused for repeat syntheses. The yield and purity of repeat batches is maintained over 5 cycles, allowing the automated synthesis of >0.5 g quantities of pure tertiary amine.