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

Abstract

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.

Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow

“…The removal of the Boc protecting group is one of the most frequently encountered transformations within the chemical and pharmaceutical community. − However, the aforementioned deprotection methodology, utilizing acids, suffers from several limitationsselectivity/compatibility, , excess amounts of reagent, , aqueous workup, , slurry formation due to vigorous off-gassing, , and “foaming-out” . Consequently, the current methodology has been extended to include a variety of conditions, including use of Lewis acids, − ionic liquids, deep eutectic liquid, Montmorillonite K10 clay, silica gel, base-mediated deprotection, , and oxalyl chloride . Despite the range of conditions available for N -Boc deprotection many of these limitations persist.…”

“… 13 Consequently, the current methodology has been extended to include a variety of conditions, including use of Lewis acids, 19 − 21 ionic liquids, 22 deep eutectic liquid, 23 Montmorillonite K10 clay, 24 silica gel, 14 base-mediated deprotection, 25 , 26 and oxalyl chloride. 27 Despite the range of conditions available for N -Boc deprotection many of these limitations persist.…”