Solvent-Mediated C3/C7 Regioselective Switch in Chiral Phosphoric Acid-Catalyzed Enantioselective Friedel-Crafts Alkylation of Indoles with α-Ketiminoesters

The first solvent-mediated tunable C3/C7 regio- and enantioselective Friedel-Crafts alkylation of 4-aminoindoles with alpha-ketimino esters has been developed. This catalysis allows the highly regioselective formation of indole C3 and C7 alkylation products, both in high yields (up to 96%) and excellent enantioselectivities (up to 99% ee). Mechanism study revealed that the hydrogen-bonding interactions of the solvents with the catalyst played a vital role for the regioselectivity switch. Furthermore, the corresponding products are indole containing unnatural alpha-amino acid derivatives bearing a quaternary stereocenter and enable many further elaborations.