Synthesis of Flavonols via Pyrrolidine Catalysis: Origins of the Selectivity for Flavonol versus Aurone

A novel
synthetic method for flavonol from 2′-hydroxyl acetophenone
and benzaldehyde promoted by pyrrolidine under an aerobic condition
in water is established. This protocol was supported by efficient
synthesis of 44 common examples and three natural products. The α,
β-unsaturated iminium ion (enimine ion E) was proved
to be the key intermediate in the reaction. H218O and 18O2 isotope tracking experiments demonstrated
that both water and the aerobic atmosphere were necessary to ensure
the transformation. The selectivity for flavonol or aurone was originated
from solvent-triggered intermediates, which were determined by UV–visible
spectra from isolated enimine. The phenol-iminium E-A is dominant in water and the ketoenamine intermediate E-B is prevalent in acetonitrile. In the presence of pyrrolidine and
oxygen, E-A leads to flavonol through E-I, a zwitterionic-like phenoloxyl-iminium ion, following the key steps
of cyclization and a [2 + 2] oxidation; E-B proceeds
through path II, a radical process induced by photolysis of E-B with both pyrrolidine and oxygen, to afford aurone. Preliminary
mechanistic studies are reported.