2-Bromopropane → (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butynyl)oxepane

Participants

Reaction Steps

To a suspension of magnesium (0.58 g, 24.2 mmol) in dry THF (10 ml) was added catalytic 1,2-dibromoethane followed by dropwise addition of a solution of isopropyl bromide (1.85 g, 15.1 mmol) in THF (5 ml). The reaction mixture was stirred for 1 hour and isoprpylmagnesiumbromide was cannulated into a 50 ml two-necked flask. A solution of 4-tetrahydropyranoyl-1-butyne (1.86 g, 12.0 mmol) in THF (5 ml) was added and the mixture was stirred for 30 minutes followed by addition of freshly prepared ZnBr2 solution (1 M, 7.25 ml, 7.2 mmol) in THF at 0° C. After 45 minutes (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.2 g, 6.0 mmol) in THF (10 ml) was added and the mixture stirred for 30 hours. The reaction was quenched with saturated aqueous NH4Cl solution at 0° C. THF was removed under reduced pressure and the residue was portioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butynyl)oxepane. The crude product was dissolved in MeOH (25 ml) and 1% HCl in MeOH (5 ml) was added. The hydrolysis of the THP group was completed in 2 hours and neutralized with saturated Na2CO3 solution and concentrated. The crude product was purified by silica gel chromotography using EtOAc-hexane (1:8) to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane (1.32 g, 75%); [α]D−74 (c 3.63, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.4-2.0 (m, 7H), 2.12 (m, 1H), 2.3 (s, 1H), 2.46 (dt, 2H), 3.65 (t, J=3.6 Hz, 2H), 3.74-3.97 (m, 2H), 4.51 (q, 1H), 6.8-7.0 (m, 4H); HRMS (EI): calcd. for C17H21O3F (M+) 292.147756 found 292.147473. Also, (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by similar procedure: [α]D+26.9 (c 2.2, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.48-2.03 (m, 8H), 2.2 (s, 1H), 2.47 (dt, 2H), 3.69 (t, J=6.9 Hz, 2H), 3.74-4.02 (m, 3H), 4.34 (dt, 2H), 6.78-7.0 (m, 4H).

Provenance & Evidence