Synthesis of substituted 2-pyridones via the Pummerer cyclization-deprotonation-cycloaddition cascade of imidosulfoxides

1-Ethanesulfinylacetylpiperidin-2-one was prepared from delta-valerolactam in two steps by heating with ethylsulfenylacetyl chloride followed by sodiu m periodate oxidation. Slow addition of the imidosulfoxide to a refluxing m ixture of toluene, acetic anhydride (10 equiv), and p-toluenesulfonic acid (1 mol %) resulted in the formation of an isomunchnone dipole which underwe nt bimolecular trapping in good yield. The stereochemical assignment of the cycloadduct was made on the basis of X-ray crystallography and is the cons equence of an endo cycloaddition with respect to the dipole. The regiochemi stry of the cycloaddition is consistent with a HOMO-dipole controlled proce ss. Several related imidosulfoxides containing a tethered alkenyl group wer e prepared and subjected to the Pummerer reaction conditions. The resulting mesoionic dipoles formed by the cyclization-deprotonation sequence undergo ready dipolar cycloaddition across the pendant olefin to afford intramolec ular cycloadducts in high yield. Exposure of these cycloadducts to acetic a nhydride in the presence of a trace of p-toluenesulfonic acid results in ri ng opening to give 5-acetoxy-substituted 2-pyridones. The lone pair of elec trons on the amide nitrogen assists in opening the oxy bridge to generate a transient N-acyliminium ion, which subsequently loses a proton. In certain cases, the amide electron pair with the oxy bridge is partially twisted fr om an antiperiplanar arrangement and a competive ring cleavage also occurs to give 5-thioethyl-substituted 2-pyridones.