A Research On Synthesis Of2,5-Diketopiperazines Via Ugi/Aza-Michael Reaction Cascades

2,5-diketopiperazines (2,5-DKPs) are very important heterocyclic compounds and widely exist in natural products and drug molecules. Many2,5-DKPs have been reported for their biological activities, such as PDE5Inhibitors, Cancer Inhibitors, Antivirals and Antibacterials, Oxytocin Antagonists and Anti-inflammatory Inhibitors, etc. At present the synthesis of2,5-DKPs are Achieved by methods such as dipeptide condensation, Ugi chemistry, amino acid condensation, Diels-Alder reaction and Wittig reaction, etc. But there is still lack of very convenient approach to provide rapid synthesis of2,5-DKPs.Diversity-Oriented Synthesis attracts great attention by academic and industry community for its rapid and efficient synthesis of a large quantity of small molecules with complicated structure. Recently, Ugi reaction has become one of the research hotspots in the organic synthesis field because of its unique charm in Diversity-Oriented Synthesis and advangtages in aspects of rapid synthesis, mild conditions, readily available raw materials and diversity of product structure.Recently, Santra et al. reported an efficient one-pot microwave assisted synthesis of DKPs via Ugi/aza-Michael cascade reaction. However, hash conditions (microwaves,300W,200℃, and18bar) was used and when a bulky isonitrile was used as the reactant, it failed to give the The expected product which left a huge space to optimize the reaction conditions.In this paper, we would like to report the design and synthesis a series of2,5-DKPs via Ugi/aza-Michael cascade reaction by using aromatic heterocyclic substituted aldehydes with a heteroatom at their β position. In the key step of the reaction cascade, the intramolecular hydrogen bonding between the heteroatom of the aldehyde potion and the NH group of the amide facilitated the aza-Michael addition and made it possible that the one-pot Ugi/aza-Michael reaction could occur under mild conditions.14novel potentially pharmaceutical2,5-DKPs were prepared by this approach. The structure of the final compounds and key intermediates were confirmed by1H-NMR,13C-NMR and MS.