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.

Comment

Besides its prevalence in extensive classes of isoquinoline alkaloids, the isoquinoline framework is an important pharmacophore of the antitumor agent saframycin-B (Y. Mikami et al. J. Pharm. Dyn. 1981, 4, 282) and topoiso­merase I inhibitor indenoisoquinoline (C. Marchand, S. Antony, K. W. Kohn, M. Cushman, A. Ioanoviciu, B. L. Staker, A. B. Burgin, L. Stewart, Y. Pommier Mol. Cancer. Ther. 2006, 5, 287). The reported 1,3-dipolar cycloaddition reaction employs a benzoxime O-(α-methyl)allyl ether, expanding the substrate scope of the procedure of Grigg which was limited to oxime O-allyl or O-crotyl ethers (R. Grigg, J. Markandu Tetrahedron Lett. 1991, 32, 279). The observed diastereoselectivity is significant, as stereochemical control of oxime formation and 1,3-dipolar cycloadditions is described as being quite poor.