A new one-pot, sequential three-component access to 3,4-diacylpyrrolo[1,2-a]pyrazine was achieved from the reaction of an α-haloketone, azide, andN-substituted pyrrole-2-carboxaldehyde under mild reaction conditions, through which a polysubstitution pattern on the pyrazine moiety of the scaffold was realized. The formation of multiple bonds (one C-C and two C-N) was enabled by this domino process involving thein situgeneration of α-iminoketones, intermolecular Mannich reaction, intramolecular imine formation, and aromatization. Construction of the relevant 3,4-diacylpyrazino[1,2-a]indole and further expansion of this chemical spaceviasynthetic elaboration of the resulting products were demonstrated as well. Preliminary biological screening of the synthesized derivatives against oral adenosquamous carcinoma cells (CAL-27) and triple negative human breast cancer cells (MDA-MB-231) led us to identify a potent hit compound (7o) having ∼3 times strongerin vitroanticancer activity than that of the anticancer agent, capecitabine.
Bibliographical noteFunding Information:
We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364, NRF-2018R1A6A1A03023718, NRF-2019R1I1A1A01061117, and NRF-2020R1A2C2005961) for generous financial support.
© The Royal Society of Chemistry 2020.
All Science Journal Classification (ASJC) codes
- Physical and Theoretical Chemistry
- Organic Chemistry