A domino annulation approach to 3,4-diacylpyrrolo[1,2-a]pyrazines: decoration of pyrazine units.

A new one-pot, sequential three-component access to 3,4-diacylpyrrolo[1,2-a]pyrazine was achieved from the reaction of α-haloketone, azide, and N-substituted pyrrole-2-carboxaldehyde under mild reaction conditions, through which polysubstitution pattern on the pyrazine moiety of the scaffold was realized. Formation of multiple bonds (one C-C and two C-N) was enabled by this domino process involving in situ generation of α-iminoketone, 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 space via synthetic 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 stronger in vitro anticancer activity than that of anticancer agent, capecitabine.