HFIP-Promoted Nenitzescu Indole Synthesis: An Application toward the Synthesis of Umifenovir

A practical solvent-mediated one-pot protocol without metal or catalyst has been developed for the synthesis of polysubstituted 5-hydroxy indole derivatives in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which plays a dual role of solvent and promoter. This method facilitates the simultaneous formation of new C-C and C-N bonds from readily available amines and benzoquinones. Unlike traditional multistep sequences that suffer from lower yields, this approach provides access to a library of derivatives in moderate to high yields. The process demonstrates excellent functional-group tolerance and was successfully performed on a gram scale. Furthermore, the utility of this strategy is highlighted by the formal synthesis of a key intermediate for Umifenovir (Arbidol), highlighting its potential for industrial pharmaceutical applications.