HFIP as Protonation Reagent and Solvent for Regioselective Alkylation of Indoles with All-Carbon Centers.

The regio- and chemoselective construction of indole bearing an all-carbon center at the C3-position, a versatile bioactive building block, by C(sp)-C(sp) formation with olefins has been achieved through utilization of hexafluoroisopropanol (HFIP) as the protonation reagent and solvent. The catalytic reactions are operationally simple and green compared with previous reports utilizing elaborated olefins and catalysts. This protocol allows for alkylation of a variety of substituted indoles with diverse of styrene type alkenes in excellent yields and with high selectivity. Application of this protocol to the synthesis of drug was pursued and with an improved yield in contrast to previous art. Catalytic kinetics and deuterium-labeling experiments suggest that the rate-determining step involves the protonation of olefin by HFIP to generate carbocation, followed by electrophilic addition to indole derivative.