A Three-Step Method for the Preparation of -Substituted 3,4-Dihydroisoquinolin-1(2)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1)-ones from 2-Bromobenzoate Precursors.

We demonstrate a general method for the preparation of diverse -substituted 3,4-dihydroisoquinolin-1(2)-one compounds through an overall three-step cross-coupling/cyclization/-deprotection/-alkylation sequence. In the first step, ethyl 2-bromobenzoates and 2-bromo-1-carboxyethyl heterocycles are cross-coupled with commercially available potassium (2-((-butoxycarbonyl)amino)ethyl)trifluoroborate to produce (hetero)aryl-substituted 3-[(-Boc-2-carboxyethyl)phenyl]ethylamines. In a subsequent two-stage process, these (hetero)arylethylamines undergo base-mediated ring closure followed by -deprotection and -alkylation to produce -substituted 3,4-dihydroisoquinolin-1(2)-ones and heteroaryl-fused -benzyl 3,4-dihydropyridin-2(1)-ones. Mechanistic work was performed to elucidate the order of transformations for the latter two-stage process. The method was also extended to the production of -benzyl isoindolin-1-one and -benzyl 2,3,4,5-tetrahydro-1-benzo[]azepin-1-one.