TBAF-Mediated [3+1] Cycloaddition of Difluorocarbene to Access gem-Difluorinated 1,2-Diazetidine Analogues as Potent Anticancer Agents

The facile synthesis of gem-difluorinated 1,2-diazetidines was achieved by metal-free [3+1] annulation between C,N-cyclic azomethine imines with difluorocarbene. A library of 30 compounds benefiting from the TBAF-mediated cyclization process could be directly assembled in moderate to good yield under mild conditions. A plausible mechanism involving the difluorocarbene pathway was proposed based on carbene trapping and control experiments. Many compounds exhibited dramatic antiproliferative activity in 4T1, A549, and HeLa tumor cell lines.

Automated summary

Gem-difluorinated 1,2-diazetidines were synthesized via metal-free [3+1] annulation between C,N-cyclic azomethine imines with difluorocarbene. A plausible mechanism involving the difluorocarbene pathway was proposed based on carbene trapping and control experiments. Many compounds exhibited significant antiproliferative activity.