Studies on aluminium mediated asymmetric Friedel–Crafts hydroxyalkylation reactions of pyridinecarbaldehydes

Abstract

The reaction of pyridinecarbaldehydes with aromatic C–H bonds mediated by chiral and achiral aluminium complexes has been investigated both experimentally and theoretically. It was found that pyridine-2-carbaldehyde activated by (R)-BINOL–AlCl reacts with e.g.N,N-dimethylaniline in a Friedel–Crafts hydroxyalkylation reaction to give the resulting alcohol in moderate yield and enantiomeric excess, whereas the pyridine-3- and -4-carbaldehydes give a diarylated product. The mechanism of the reaction has been investigated using theoretical calculations. The calculations show that the uncatalyzed reaction proceeds via a concerted, one-step mechanism, having a four-membered transition state with an energy barrier of 81 kcal mol⁻¹. However, for the Lewis acid-mediated reaction using AlCl₃ as the Lewis acid, the reaction proceeds through a zwitterionic intermediate in which the transition-state energy is significantly reduced. For the reaction of pyridine-2-carbaldehyde, the aluminium Lewis acid can coordinate in both a mono- and bidentate fashion to the substrate. Furthermore, two Friedel–Crafts intermediates have been found depending on the orientation of the incoming aromatic compound. Several transition states have been calculated for the formation of the Friedel–Crafts intermediates starting from the two different coordination modes of pyridine-2-carbaldehyde to AlCl₃. The lowest energy for the reaction has been calculated to be 5.6 kcal mol⁻¹ for pyridine-2-carbaldehyde activated by AlCl₃ in a monodentate fashion. The mechanistic aspects of these observations will be discussed.