反应详情

温度

-78 °C

A solution of n-butyllithium (1.25 mL of a 2.5 M soln in hexanes, 3.12 mmol) was added to a stirred solution of 2,2,6,6-tetramethylpiperidine (0.56 mL, 3.33 mmol) in dry THF (4.37 mL) at 0° C. under N2. Separately, a mixture of methyl trans-3-(4-methoxyphenyl)cyclobutanecarboxylate (INTERMEDIATE 14, Step E) (0.200 g, 0.908 mmol) and dibromomethane (0.22 mL, 3.12 mmol) in dry THF (4.37 mL) was cooled to −78° C. under N2. After 30 min, the LiTMP solution was cooled to −78° C. and added to the ester/CH2Br2 solution dropwise via cannula. After 15 min a cold (−78° C.) solution of lithium bis(trimethylsilyl)amide (3.12 mL of a 1 M soln in THF, 3.12 mmol) was added dropwise via cannula. The mixture was allowed to warm to −20° C. and then recooled to −78° C., and a solution of sec-butyllithium (3.39 mL of a 1.4 M soln in cyclohexane, 4.74 mmol) was added dropwise. The mixture was then warmed to −20° C. and a solution of n-butyllithium (1.13 mL of a 2.5 M soln in hexanes, 2.82 mmol) was added. The mixture was warmed to room temperature, stirred for 1 h and then quenched over a 20 min period into a stirred solution of acidic methanol at 0° C. (prepared by slow addition of acetyl chloride (2.01 mL, 28.3 mmol) to ice-cooled dry MeOH (10.2 mL). The mixture was diluted with Et2O (40 mL) and washed with satd sq. NaHCO3. The aqueous phase was re-extracted with Et2O (2×40 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl [trans-3-(4-methoxyphenyl)cyclobutyl]acetate, as a colorless oil. Rf=0.55 (20% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.18 (d, J=8.4 Hz, 2H); 6.87 (d, J=8.4 Hz, 2H); 3.80 (s, 3H); 3.69 (s, 3H); 3.59-3.54 (m, 1H); 2.74-2.71 (m, 1H); 2.62 (d, J=7.9 Hz, 2H); 2.38-2.31 (m, 2H); 2.19-2.13 (m, 2H).

1. temperatureto warm to −20° C.
2. customrecooled to −78° C.
3. temperatureThe mixture was then warmed to −20° C.
4. temperatureThe mixture was warmed to room temperature
5. customquenched over a 20 min period into a stirred solution of acidic methanol at 0° C. (
6. washwashed with satd sq
7. extractionThe aqueous phase was re-extracted with Et2O (2×40 mL)
8. dry with materialthe combined organic extracts were dried (MgSO4)
9. concentrationconcentrated in vacuo
10. customto give the crude product
11. customThis was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL)