Reaction Steps
Under nitrogen, a solution of 4.86 g (30 mmol) of carbonyl diimidazole in 50 mL of methylene chloride was treated with 3.63 g (30 mmol) of 2-ethylaniline (Aldrich). The reaction was allowed to stir at ambient temperature for 90 min prior to the addition of 4.80 g (30 mmol) of L-norleucine-N-methoxy-N-methylamide from Step 3. The reaction was stirred overnight, filtered and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethylacetate/hexane (40:60) gave 2.45 g (25%) of the 2-ethylphenyl urea of L-norleucine-N-methoxy-N-methylamide as a colorless solid: NMR (CDCl3) δ 0.88 (t, J=7 Hz, 3H), 1.14 (t, J=8 Hz, 3H), 1.30-1.38 (m, 2H), 1.38-1.60 (m, 2H), 1.63-1.80 (m, 2H), 2.49 (t, J=7 Hz, 2H), 2.56 (t, J=8 Hz, 2H), 3.20 (s, 3H), 3.82 (s, 3H), 4.18-4.27 (m, 1H), 4.96 (5, J=8 Hz, 1H), 6.77 (br s, 1H), 7.05-7.22 (m, 2H), 7.32-7.43 (m, 1H), 7.54 (d, J=8 Hz, 1H). A solution of 2.37 g (7.4 mmol) of this urea in 50 mL of anhydrous THF/ether (1:1) was treated with 9.2 mL (9.2 mmol) of 1M LAH in ether at ambient temperature. The reaction was allowed to stir for 90 min and was slowly treated with a solution of 1.77 g (13 mmol) of KHSO4 in 45 mL of water. This mixture was rapidly stirred for 3 hr and then the layers were separated. The aqueous layer was extracted three times with ether and the extracts were combined with the organic layer. The etheral solution was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was dissolved in 30 mL of methylene chloride, treated with 0.5 mL of TFA, and stirred at reflux for 3 hr. The reaction was cooled to ambient temperature, washed with NaHCO3 (sat), dried (MgSO4), and concentrated in vacuo to give 1.8 g (100%) of 1-(2-ethylphenyl)-4-butyl-1,3-dihydro-2H-imidazol-2-one as a colorless oil: NMR (CDCl3) δ0.92 (t, J=7 Hz, 3H), 1.17 (t, J=7, Hz, 3H), 1.38 (m, J=7 Hz, 2H), 1.58 (m, J=7 Hz, 2H), 2.46 (t, J=7 Hz, 2H), 2.58 (q, J=7 Hz, 2H), 6.06 (s, 1H), 7.16-7.30 (m, 2H), 7.30-7.40 (m, 2H).
