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

• Published in: Journal of organic chemistry 2023-02, Vol.88 (4), p.2589-2598
• Main Authors: Freeman, Emily E., Jackson, Randy, Luo, Jessica, Somwaru, Rajen, Sons, Alex A., Bean, Andrew, Buckle, Ronald N., Herr, R. Jason
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.2c02670

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.