| 56% |
Stage #1: 1-allyl-2-bromobenzene With iodine; magnesium In tetrahydrofuran at 70℃; for 0.75h; Inert atmosphere; Reflux;
Stage #2: With copper(I) bromide dimethylsulfide complex In tetrahydrofuran at -40℃; for 0.75h; Inert atmosphere;
Stage #3: (-)-Verbenone In tetrahydrofuran at -78 - 20℃; for 12h; Inert atmosphere; diastereoselective reaction; |
4.5.1. (1S,4S,5R)-4-(2-allylphenyl)-4,6,6-trimethylbicyclo[3.1.1]heptan-2-one (1g)
To a flame-dried 20 mL microwave vial was added magnesium turnings (52.8 mg, 2.2 mmol, 1.2 equiv) and a catalytic amount of I2 (ca 5 mg). The reaction vessel was capped, evacuated, and backfilled with N2 and THF (4.0 mL, 0.5 M) was added to the reaction vessel. The reaction vessel was then moved to a 70 °C pre-heated oil bath and stirred for 10 min. The reaction vessel was then removed from the oil bath and to the reaction mixture was added 1-allyl-2-bromobenzene (0.3 mL, 2.0 mmol, 1.1 equiv) dropwise over 15 min as to maintain a gentle reflux. The reaction vessel was then moved back to a 70 °C oil bath and stirred for 30 min. The reaction vessel was then removed from the oil bath and cooled to ambient temperature. In a separate flame-dried 20 mL microwave vial equipped with a magnetic stir bar was added CuBr·SMe2 (41.3 mg, 0.2 mmol, 10 mol %). The reaction vessel was evacuated and backfilled with N2 before THF (4 mL, 0.45 M) was added to the reaction vessel. The reaction mixture was then cooled to -40 °C in a dry ice-acetonitrile bath and the previously prepared Grignard solution was added dropwise over 15 min. The reaction mixture was stirred at -40 °C for 30 min before it was cooled to -78 °C in a dry ice-acetone bath and verbenone (SI-1) (0.28 mL, 1.8 mmol, 1.0 equiv) was added dropwise. The reaction mixture was stirred for 12 h and slowly warmed to ambient temperature. To the reaction mixture was added sat. aq. NH4Cl (10 mL) and Et2O (10 mL). The organic phase was separated and the aqueous phase was extracted with Et2O (2×10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure by rotary evaporation. Purification by flash column chromatography on silica gel (10% Et2O/hexanes) afforded 1g (270.3 mg, 56%) as a yellow oil. Rf: 0.36 (10% Et2O/hexanes) [α]20D: -16.0° (c 1.0, CHCl3) 1H NMR (400 MHz, CDCl3): δ 7.28 (dd, J=7.6, 1.6 Hz, 1H), 7.19-7.10 (m, 2H), 7.00 (d, J=7.2 Hz, 1H), 5.99 (ddt, J=16.4, 10.0, 6.0 Hz, 1H), 5.14-5.05 (m, 2H), 3.51 (d, J=6.0 Hz, 2H), 2.99 (s, 2H), 2.75-2.70 (m, 2H), 2.55 (at, J=4.8 Hz, 1H), 1.54 (s, 3H), 1.53-1.51 (m, 1H), 1.50 (s, 3H), 1.14 (s, 3H) 13C NMR (101 MHz, CDCl3): δ 213.4, 149.6, 138.1, 137.8, 132.9, 126.0, 125.9, 124.9, 116.5, 55.9, 52.8, 50.6, 40.1, 39.7, 38.5, 30.2, 27.9, 27.0, 25.9 IR (cm-1): 2925, 1711, 1637, 1483, 1255, 1202, 987, 914, 760, 503, 467 GC-MS (m/z): [M] calc’d for C19H24O: 268.2; found: 268.1. |
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