Aniline → N-[2-(Isobutylamino)-4-(3-methylbutoxy)phenyl]-2-(3-methoxyphenoxy)acetamide

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Reaction Steps

A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 49b (11.0 g, 30.7 mmol), THF (110 mL), and MeOH (30 mL). To the resultant solution was added isobutyraldehyde (3.10 g, 3.92 mL, 43.0 mmol), and the mixture stirred 15 min at rt. Meanwhile, in a 250 mL flask fitted with a stir-bar and septum with an Ar inlet, NaCNBH3 (1M in THF, 43 mL, 43.0 mmol) was added to MeOH (100 mL) followed by ZnCl2 (1M in Et2O, 21.5 mL, 21.5 mmol) forming a cloudy mixture. After stirring 20 min, this mixture was added to the above aniline solution. The mixture was stirred overnight at rt. Another 4.0 mL isobutyraldehyde was added, followed by a second addition of the same volume of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred at rt overnight. Another 2 mL of isobutyraldehyde was then added, and the mixture stirred overnight again. The cloudy solution was diluted with EtOAc (500 mL) and washed with saturated NaHCO3 (2×400 mL) and brine (250 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a waxy, orange solid. The solid was collected with hexanes (20 mL) and rinsed with hexanes (2×10 mL). The material dried to give 10.7 g of 50b as a pale orange solid. A second crop of 1.20 g was collected (94%). 1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1H), 7.31-7.23 (m, 1H), 7.16 (d, 1H), 6.65-6.56 (m, 3H), 6.33-6.24 (m, 2H), 4.70 (s, 2H), 3.96 (t, 2H), 3.82 (s, 3H), 3.75 (bt, 1H), 2.84 (t, 2H), 1.83 (nonet, 2H), 1.67 (qt, 2H), 0.97 (d, 6H), 0.95 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 6.9 min.

Provenance & Evidence