1,2,3,4-Tetrahydroisoquinoline → tert-Butyl 4-iodo-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate

Participants

Reaction Steps

A 100 mL flask was charged with 3-(tert-butoxycarbonyl)benzoic acid (Matrix, 1.75 g, 7.87 mmol), palladium(II) acetate (0.177 g, 0.787 mmol), iodobenzene diacetate (2.54 g, 7.87 mmol), iodine (2.00 g, 7.87 mmol), and tetrabutylammonium iodide (2.91 g, 7.87 mmol). DCE (30 mL) was added and the dark reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was concentrated in vacuo, diluted with 2M aq. sodium carbonate solution, and then extracted with ether (2×). The aqueous layer was made acidic with concentrated HCl and then extracted with EtOAc (2×). The pooled EtOAc extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.7 g, 62%) which was used directly without further purification. A 200 mL round bottom flask was charged with crude 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.7 g, 4.88 mmol) and HATU (2.23 g, 5.86 mmol). THF (30 mL), DMF (30.0 mL), and 2,6-lutidine (1.1 mL, 9.77 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Next, 1,2,3,4-tetrahydroisoquinoline (0.93 mL, 7.3 mmol) was then added. After stirring at room temperature 1 h, the reaction mixture was suspended in EtOAc, and then washed with sat. aq. sodium bicarbonate solution, 10% aq. LiCl solution, and then sat. aq. bicarbonate solution again. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 120 g column eluting with 0-40% EtOAc/hexanes) to give the title compound (1.46 g, 65%) as a white foam. 1H NMR (CDCl3) δ 7.96-7.90 (m, 1H), 7.81-7.80 (m, 1H), 6.70-6.67 (m, 1H), 7.27-7.13 (m, 4H), 5.09-4.83 (m, 1H), 4.45-4.33 (m, 1H), 4.06-4.01 (m, 1H), 3.50-3.44 (m, 1H), 3.05-2.83 (m, 2H), 1.58 (s, 9H); MS(ESI+) m/z 464.1 (M+H)+.

Provenance & Evidence