The secondary amine mediated Baylis-Hillman reaction of substrates 1 have been found to proceed via a tandem Michael addition/intramolecular aldol
followed by a slow elimination step; it was also observed that similar processes
could be effected using phosphines and thiols as mediators. These reactions are
highly substrate dependent, with the best results being obtained for the formation of 5 and 6-membered products 2 and 3 using thiol or thiolate nucleophiles. Amine and phosphine mediated cyclisations were found to be problematic in several cases but were still effective methods for the formation of 5-7 membered compounds for example 4.
(a) Piperidine, TolSH or PR₃; CDCl₃ or CHCl₃; r.t. to reflux
R = Ph, EtO or TolS; X = Piperidyl, TolS or PR₃; n = 1, 2, 3, 4 or 5
Mechanistic investigations into the reaction of amines found that piperidine was the most effective catalyst of the amines investigated. Intermediates 5 and 6 were shown to be stable long-lived species by NMR and X-ray crystallographic data for 7 was also obtained.