Synthesis and spectroscopic investigation of substituted piperazine-2,5-dione derivatives

The piperazine-2,5-dione moiety is a useful scaffold for functionalisation to generate bioactive molecules. Synthetic methods for accessing substituted piperazine-2,5-diones involve cyclising dipeptides or building from the already established core. Utilising the latter method, we have developed procedures to condense a variety of methoxylated benzaldehydes to exclusively form (Z,Z)-(benzylidene)piperazine-2,5-diones 7. This methodology can easily be utilised to form both homo- and heterodimeric substituted piperazine-2,5-diones. Subjecting these compounds to hydrogenation affords two isomers. We detail simple NMR analyses that allow for identification of the cis or trans isomers. These analyses, combined with X-ray crystallography have shown that under the hydrogenation conditions used the cis isomer forms as the major product. The synthetic methodology combined with spectral analysis provides a valuable understanding of piperazine-2,5-dione properties.