Synthesis of Isoquinolines via 1,3-Dipolar Cycloaddition-Heck Coupling

Significance

The synthesis of dihydroisoquinoline derivatives by a three-component coupling reaction of aldehydes, allyloxyamines, and maleimides is reported. Key steps include i) initial formation of a stable oxime O-allylic ether, ii) intramolecular Pd(II)-catalyzed [2,3]-sigmatropic rearrangement to a nitrone, iii) a 1,3-dipolar cyclo­addition of the resulting nitrone to a maleimide dipolarophile, and iv) an intramolecular Heck reaction. The 1,3-dipolar cycloaddition was deduced to proceed intramolecularly on the basis of crossover experiments involving specific matching of allylic oximes from the set of substrates designated 1-4. The observed diastereomeric enrichment of the tetrahydroquinoline product compared to the precursor iodoolefin was rationalized by an equilibrium between diastereomers, for which a mechanism is not proposed.