Aniline → 2-(3-Ethoxyphenoxy)-N-[4-hydroxy-2-(isobutylamino)phenyl]acetamide

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Reaction Steps

A 500 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 64 (9.20 g, 30.4 mmol), THF (100 mL), and MeOH (30 mL). To the resultant solution was added isobutyraldehyde (3.07 g, 3.89 mL, 42.6 mmol), and the mixture stirred 10 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 mmol) was added to MeOH (80 mL). ZnCl2 (1M in Et2O, 21 mL, 21 mmol) was next added forming a cloudy mixture which was stirred for 10 min. The mixture was then added to the above aniline solution. The reaction stirred overnight at rt. Another 1.0 mL isobutyraldehyde was added, followed by a second portion of 25% of the original amount of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred at rt overnight. Another 0.5 mL of isobutyraldehyde was then added, and the mixture stirred overnight again. The cloudy solution was diluted with EtOAc (300 mL) and washed with saturated NaHCO3 (2×250 mL) and brine (150 mL). The solution was filtered through phase separation paper and concentrated to 12.1 g of a dark oil. The crude oil was chromatographed on silica gel with the product eluting with 25-33% EtOAc in hexanes. The product fractions were concentrated to give 10.2 g of 65b as a tan solid (85%). 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.24 (m, 1H), 6.97 (d, 1H), 6.64-6.52 (m, 3H), 6.16 (d, 1H), 6.09 (dd, 1H), 4.67 (s, 2H), 4.05 (qt, 2H), 2.77 (d, 2H), 1.78 (nonet, 1H), 1.43 (t, 3H), 0.92 (d, 6H) ppm. HPLC analysis (10:10:80 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.3 min.

Provenance & Evidence