2,5-Diketopiperazines via Intramolecular N-Alkylation of Ugi Adducts: A Contribution to the Synthesis, Density Functional Theory Study, X-ray Characterization, and Potential Herbicide Application

To investigate the herbicidal potential of 2,5-diketopiperazines (2,5-DKPs), we applied a known protocol to produce a series of 2,5-DKPs through intramolecular N-alkylation of Ugi adducts. However, the method was not successful for the cyclization of adducts presenting aromatic rings with some substituents at the ortho position. Results from DFT calculations showed that the presence of voluminous groups at the ortho position of a benzene ring results in destabilization of the transition structure. Lower activation enthalpies for the S(N)2-type cyclization of Ugi adducts were obtained when bromine, instead of a chlorine anion, is the leaving group, indicating that the activation enthalpy for the cyclization step controls the formation of the 2,5-DKP. Some Ugi adducts and 2,5-DKPs formed crystals with suitable qualities for single-crystal X-ray diffraction data collection. Phytotoxic damage of some 2,5-DKPs on leaves of the weed Euphorbia heterophylla did not differ from those caused by the commercial herbicide diquat.

Automated summary

Experimental findings indicated that the presence of bulky substituents at the ortho position of a benzene ring hindered the synthesis of 2,5-DKPs, while bromine as a leaving group was more effective than chlorine in lowering the activation enthalpy for cyclization step, promoting the formation of 2,5-DKPs.