Construction of bicyclic tetrahydroisoquinolinones by combination of an IMDAF-ring cleavage reaction of N-allyl-2-furan-2-yl-acetamides

The intramolecular Diels-Alder reaction of furanyl amides derived from 2-fu rylacetic acid has been examined. Substrates containing either an imide or tertiary amide linkage between the furan and the dienophile underwent smoot h cycloaddition upon thermolysis. By varying the reaction conditions, eithe r the primary cycloadduct or the ring-opened and acetylated product could b e isolated in excellent yield. The stereochemical outcome of the IMDAF cycl oaddition has the side arm of the tethered alkenyl group oriented syn with respect to the oxygen bridge. Semi-empirical AM1 calculations show that the exo-cycloadduct is 11 kcal lower in energy than the corresponding endo add uct and, presumably, some of this energy difference is reflected in the tra nsition state for the cycloaddition. The IMDAF reaction of N-allyl-[2-(3,4- dimethoxyphenethyl)]-2-furanyl-2-yl-acetamide proceeded in 90% yield upon h eating in xylene. The 4+2-cycloadduct undergoes ring-opening on treatment w ith base and the resulting alcohol was converted into the corresponding ben zyl ether. Raney nickel reduction followed by Bischler-Napieralski cyclizat ion furnished the tetracyclic skeleton of the berberine alkaloids.