Reaction Steps
A suspension of 3-(4-benzyloxyphenyl)-8-chloro-isochromen-1-one (1.7 g, 4.7 mmol) and 2,4-difluorobenzylamine (0.75 mL, 6.3 mmol) was prepared in toluene (25 mL) in a 100 mL round-bottomed flask under nitrogen. To the resulting suspension was added a solution of methyl aluminoxane (5.0 mL, of a 1.5 M solution in toluene, 7.5 mmol). Gas evolution was observed as the aluminoxane solution was added. The resulting suspension was then heated to reflux. As the solution came to reflux the solids dissolved to afford a brown solution. After stirring at reflux for 16 hours, an aliquot of the reaction was worked up with aqueous HCl, and analyzed by TLC. There was no visible 8-chloro-3-(4-phenoxyphenyl)-isochromen-1-one, and there were two product spots visible. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (50 mL), and diluted with EtOAc (100 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (50 mL), saturated aqueous NaHCO3 (30 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white foam. The crude foam was purified by silica gel column chromatography eluting with a gradient from 0% to 30% EtOAc/hexane. Two product peaks were collected from the column: The first peak that eluted was concentrated to afford 3-(4-benzyloxyphenyl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one, a compound of formula (Id), (1.68 g, 73% yield); 1H-NMR (400 MHz, CDCl3): δ 7.51-7.48 (2H, m), 7.46-7.33 (6H, m), 7.11-7.07 (2H, m), 7.04-6.96 (1H, m), 6.95-6.91 (2H, m), 6.78-6.71 (1H, m), 6.66-6.59 (1H, m), 6.39 (1H, s), 5.17 (2H, s), 5.10 (2H, s); and the second peak that eluted was concentrated to afford 2-[2-(4-benzyloxyphenyl)-2-oxoethyl]-6-chloro-N-(2,4-difluorobenzyl)benzamide, a compound of formula (W) (533 mg, 22% yield); 1H-NMR (400 MHz, CDCl3): δ 7.78 (2H, d, J=8.8 Hz), 7.45-7.30 (5H, m), 7.26-7.14 (3H, m), 7.00-6.93 (3H, m), 6.71 (1H, t, J=6.3 Hz), 6.56-6.49 (1H, m), 6.45-6.37 (1H, m), 5.12 (2H, s), 4.40 (2H, d, J=6.3 Hz), 4.16 (2H, s).
