Pepsin‐Catalyzed Friedel–Crafts Alkylation of Indoles, 7‐Azaindoles, and Pyrroles With Enamides

ABSTRACT A pepsin‐based biocatalytic system has been developed for the Friedel–Crafts alkylation of indoles and pyrroles with enamides. In an acetic acid/water mixture (4:1, v/v), the model reaction of indole with 1‐vinylpyrrolidin‐2‐one proceeded efficiently at 50°C and furnished the C3‐alkylation product in up to 99% yield. Indoles bearing a variety of substituents were tolerated, and several other enamides also participated, their reactivity being governed by electronic and steric factors. 7‐Azaindoles, in which the pyridine nitrogen lowers the nucleophilicity of the pyrrole ring, proved less effective under these conditions. Pepsin was readily recovered from the aqueous phase and could be applied in 10 consecutive cycles for the reactions of indole and pyrrole, with the yield staying above 90% in every cycle. A plausible mechanism, in which the active‐site residues Asp32 and Asp215 cooperate to activate the enamide and the heteroaromatic substrate through general acid–base catalysis, is proposed. This work provides a metal‐free and readily recyclable biocatalytic route to functionalized indole derivatives.