A cyclative cleavage approach to the solid phase synthesis of 2-oxo-1,4-piperazines

A new facile solid phase synthesis of 2-oxo-1,4-piperazines is described. α-N-Boc-amino aldehydes, which were generated in situ by oxidation of commercially available α-amino alcohols promoted by a polymer supported bromite, were used for the reductive amination of Merrifield-resin bound amino acids. N-substitutions of the resulting secondary amine followed by Boc removal and finally, basic promoted cyclative cleavage affords trisubstituted 2-oxo-1,4-piperazines in good yields and excellent purity. The procedure utilizes readily available building blocks and is amenable to generate large libraries in a discrete manner.