On the molecular structure and geometry of pyridylalkylamine–H+ complexes: application to catalytic enantioselective hydroxyalkylation of indoles

Abstract

The protonation of 2-pyridylalkylamines (PAA) was investigated through quantum chemical calculations at a DFT level of theory in dichloromethane solution. Two different PAA–H⁺ species and a dynamic equilibrium between protonated forms were evidenced. The overall geometry of the PAA–H⁺ promoters is strongly influenced by the nature of the moiety and the absolute configuration of the pseudobenzylic stereocenter. Thus, PAA–H⁺ complexes were used as organocatalysts in the enantioselective hydroxyalkylation of indole derivatives. The combination of PAA, a strong acid and a soft counter-ion was found to be a mandatory parameter to achieve high yields and selectivities allowing hydroxyalkylation of both N–H and N-protected indoles using a unique catalytic system.