Metal-Tuned Synthesis of Isoindolyl and Isoquinolinyl Phosphonates

Significance

Reported is an intramolecular annulation of α-amino (alkynylphenyl)methylphosphonates to either 1,2-dihydroisoquinolin-1-yl­phosphonates or to 2H-isoindol-1-ylphosphonates, depending on the choice of catalyst. The Lewis acid AgOTf (Method A) leads to the former product via an 6-endo cyclization, whereas the Pd(II) catalyst, Pd(PhCN)₂Cl₂ (Method B) leads to the latter product via a 5-exo cyclization. The factors affecting this regioselectivity were not addressed but may be speculated to be due to distinctly different coordination and cation stabilizing properties of Ag⁺ vs Pd⁺². The starting material is accessible by a three-component coupling of aldehydes, amines, and diethyl phosphate catalyzed by Lewis acids (J. Wu et al. Org. Biomol. Chem. 2006, 4, 1663). The isoindole and isoquinoline products were obtained in moderate to excellent yields and the substrate scope was sufficiently studied. A lower catalyst loading resulted in lower yields of products.