A novel one-pot five-component synthesis of tetrahydro-pyrrolo[3,4-b] pyridine-5-one via ugi/aza-diels–alder tandem reaction

Abstract

A novel five-component domino processes to tetrahydro-pyrrolo[3,4-b] pyridine-5-one (8) were developed. Reaction of 5-phenyloxazole-2-carbaldehyde (1), p-toluidine (2), (Z)-4-methoxy-4-oxobut-2-enoic acid (3), and t-butyl isocyanide (4) in methanol at 60 °C provides an efficient access to the drug-like bicycle compound (8) in a good yield. In this one-pot process, a traditional oxo-bridged tricycle intermediate was formed via Ugi/ara-Diels–Alder tandem reaction and then the solvent, methanol, sequentially attacks and cuts off the oxo bridge under mild conditions via SN2 reaction. Formation of one C–N, two C–O, and three C–C bond with the triple domino sequence (Ugi/IMDA/SN2) is involved in this new scaffold generating reaction. The operational simplicity and maximizing the buildup of structural complexity makes this novel multicomponent reaction valuable in diversity-oriented synthesis of tetrahydro-pyrrolo[3,4-b]pyridine-5-one.