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

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.