1-Bromo-3-chlorobenzene → 2-tert-butyl 3-methyl 6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylate

Participants

Reaction Conditions

Reaction Steps

2-tert-Butyl 3-methyl 6-hydroxy-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (200 mg, 0.65 mmol), m-chloro-phenyl bromide (103 mg, 0.54 mmol), 2, 2, 6, 6-tetramethylheptane-3,5-dione (TMHD, 10 mg, 0.054 mmol), Cs2CO3 (326 mg, 1.00 mmol), and CuCl (27 mg, 0.27 mmol) were mixed together in NMP (1 mL) and heated to 120° C. for 6 h. The reaction was then diluted with MTBE and filtered over celite. The filtrate was washed with 1 N HCl, 1 N NaOH, and brine. The organic was dried over Na2SO4 and concentrated before loading on a Biotage silica column (12 m) and eluting with 10% Acetone/Hexanes to give 2-tert-butyl 3-methyl 6-(3-chlorophenoxy)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate as a pale yellow oil (113 mg, 50%). This material was then taken up in 1 mL of a mixture of THF/H2O (3:1) and LiOH (70 mg, 1.62 mmol) was added. The reaction stirred overnight at rt, before it was concentrated and quenched with 1 N HCl. The product was then extracted with EtOAc (3×). The combined extracts were dried over Na2SO4 and concentrated to give a pale yellow foam (100 mg, 92%). MS m/e 402.9 (M−−H).

Provenance & Evidence