Aniline → N-[4-Ethoxy-2-(isobutylamino)phenyl]-3-phenylpropanamide

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Reaction Steps

A 250 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 76 (3.30 g, 11.6 mmol), THF (35 mL), and MeOH (10 mL). To the resultant solution was added isobutyraldehyde (1.17 g, 1.48 mL, 16.2 mmol), and the mixture stirred 15 min at rt. Meanwhile, in a 100 mL flask fitted with a stir-bar and septum with an Ar inlet, NaCNBH3 (1M in THF, 16.2 mL, 16.2 mmol) was added to MeOH (10 mL). ZnCl2 (1M in Et2O, 8.1 mL, 8.1 mmol) was added next forming a cloudy mixture. After 15 min, this mixture was added to the above aniline solution. After stirring at rt 2.3 hr, another 0.3 mL isobutyraldehyde was added, followed by a second portion of 20% of the original amount of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred overnight at rt. The cloudy solution was diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (2×125 mL) and brine (100 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a yellow solid. The solid was triturated with hexanes:EtOAc 20:1 (20 mL), filtered, pressed with a rubber dam, and rinsed with hexanes (2×10 mL) to give 3.5 g of 77 as a yellow solid (89%). 1H NMR (Two isomers evident ˜3:2) (300 MHz, CDCl3): δ 7.38-7.18 (m, 5H), [6.87 (d, 0.6H), 6.78 (d, 0.4H)], [6.62 (s, 0.6H), 6.48 (s, 0.4H)], 6.24-6.12 (m, 2H), [4.02 (qt, 1.2H), 4.00 (qt, 0.8H)], [3.07 (t, 1.2H), 2.92 (t, 0.8H)], [2.86 (d, 1.2H), 2.84 (d, 0.8H)], [2.71 (t, 1.2H), 2.40 (t, 0.8H)], [1.85 (nonet, 0.4H), 1.84 (nonet, 0.6H)], [1.41 (t, 1.2H), 1.38 (t, 1.8H)], 0.94 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.5 min.

Provenance & Evidence