On-Demand Selection of the Reaction Path from Imino Diels-Alder to Ene-Type Cyclization: Synthesis of Epiminopyrimido[4,5-b]azepines

Article abstract of DOI:10.1002/ejoc.201301318

Controlling the mode of reaction of a reactive intermediate such as an imine or iminium ion should enable the on-demand selection of the final products from the same starting materials. The successful execution of such a strategy will reduce the time required to prepare diverse scaffolds. The imines derived from 4-(allylamino)pyrimidine-5-carbaldehydes and anilines undergo Diels-Alder reactions to give pyrimido[4,5-h][1,6]naphthyridines in high yields. A complete switch from the intramolecular aza-Diels-Alder (IADA) path to an ene-type cyclization reaction was achieved by simply adjusting the reaction conditions (amount of acid catalyst, solvent, and temperature). This newly introduced ene-type cyclization reaction was used to prepare a series of epiminopyrimido[4,5-b]azepines. To gain insight into the mechanism of the two reaction pathways, a DFT study was carried out. Theoretical calculations showed that under acidic conditions an iminium intermediate favors the low-energy IADA pathway, which proceeds in a [4⁺ + 2] fashion. When acid is absent, the neutral imine intermediate favors the thermal ene-type cyclization reaction, which takes place by transfer of an allylic proton from the allylic amine to imine, followed by a barrierless nucleophilic addition process between the in-situ-generated anionic allylic amine and iminium ion. Amine addition to the alkene finally gives the epiminopyrimido[4,5-b]azepines. A complete switch from an intramolecular aza-Diels-Alder (IADA) reaction to an ene-type cyclization was achieved simply by adjusting the reaction conditions. A DFT study was carried out to gain insight into the mechanisms of the two reaction pathways. A series of epiminopyrimido[4,5-b]azepines were prepared using this newly introduced ene-type cyclization reaction.