On the Ring-Opening Reaction of Thiophene-1,1-dioxides and the Intramolecular Diels-Alder Reaction of Azanona- and AzadecatrienesI

Abstract: Substituted thiophene-1,1-dioxides were synthesized and their ring-opening reactions with omega-unsaturated secondary amines were investigated; this led to a synthetic route to azatrienes and to the preparation of some polyhydroisoindoles and polyhydroisoquinolines via an intramolecular Diels-Alder reaction. By using 2-substituted pyrrolidines and piperidines various tetrahydrobenzo[f]indolizidines, benzo[b]quinolizidines, tetrahydrobenzo[a]indolizidines and tetrahydro[a]pyrrolizidines could be synthesized via the ring-opening of 3-bromo-2,5-dimmethylthiophene-1,1-dioxide and a subsequent intramolecular Diels-Alder reaction. Aminoalcohols such as L-prolinol worked well and a diastereo- selective synthesis of substituted tetrahydro[a]pyrrolizidines was achieved. Asymmetric induction was observed in the L-prolinol induced ring-opening of 3-bromo-5-ethyl-2-isopropylthiophene-1,1- dioxide. A multivariate optimization procedure involving the use of response surface methodologies was undertaken to improve yields in the ring-opening reaction of 2-alkyl-3-bromo-5-methylthiophene- 1,1-dioxides. The mechanism of the ring-opening reaction was studied by isotope labeling and measure- ments of kinetic isotope effects. Semiempirical and ab initio calculations were made on transition states in order to explain stereoselectivities of the intramolecular Diels-Alder reaction in the azanona- and aza- decatriene series.