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