Selective Synthesis of 3-(α-Fluorovinyl)indoles and 3-Acylindoles via the Cascade Reactions of 1-Phenylpyrazolidinones with α,α-Difluoromethylene Alkynes

Presented herein is a selective synthesis of 3-(alpha-fluorovinyl)indoles and 3-acylindoles via the coupling of 1-phenylpyrazolidinones with alpha,alpha-difluoromethylene alkynes. Mechanistically, the formation of 3-(alpha-fluorovinyl)indoles is resulted from a cascade process including Rh(III)-catalyzed ortho-C-H bond cleavage, regioselective triple bond insertion, pyrazolidinone ring-opening, indole ring-formation and HF elimination. Interestingly, when this reaction was carried out in CH3OH/H2O instead of CH3CN, the in situ formed 3-(alpha-fluorovinyl)indoles readily undergo a hydration process to afford 3-acylindole derivatives. This protocol features with controllable selectivity, simultaneous formation of both the heterocyclic scaffold and the monofluoroalkenyl moiety, atom-economy, substrate diversity, good functional group tolerance and redox-neutral reaction conditions. Anticancer screening of selected products against two human cancer cell lines demonstrated their potential as lead compounds for drug development.