| 87% |
Stage #1: tert-butyl propionate With n-butyllithium; diisopropylamine; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran; hexane at -78 - 0℃; for 0.25h;
Stage #2: phenyl propionate In tetrahydrofuran; hexane at -78℃; for 1h; |
2
A 2.58 M solution of w-butyllithium in hexane (71.0 mL, 183 mmol) and a 2.41 M solution of w-butyllithium in hexane (33.2 mL, 80 mmol) was added dropwise to a solution of hexamethyldisilazane (58.4 mL, 275 mmol) in THF (160 mL) at 0 °C and the mixture was stirred at 0 °C for 45 min to prepare lithium hexamethyldisilazide (as a hexane and THF solution). A 2.42 M solution of w-butyllithium in hexane (69.0 mL, 167 mmol) and a 2.41 M solution of w-butyllithium in hexane (37.8 mL, 91 mmol) were added dropwise to a solution of diisopropylamine (36.3 mL, 258 mmol) in THF (160 mL) at -78 °C. The resulting mixture was warmed to 0 °C, stirred for 10 min and recooled to -78 °C. A solution of tert- butyl propionate (32.5 g, 250 mmol) in THF (90 mL + 35 mL x 2 wash) was added to the above lithiumdiisopropylamide solution. The resulting mixture was stirred at -78 °C for 15 min. A freshly prepared solution of lithium hexamethyldisilazide in hexane and THF (323 mL, 30 mL x 2 wash with THF) was added and then after 5 min a solution of phenyl propionate (39.4 g, 263 mmol) in THF (50 mL + 25 mL x 2 wash) was added to the reaction mixture at -78 °C. The resulting mixture was stirred at -78 °C. After 1 h, saturated ammonium chloride aqueous solution (150 mL) at -78 °C. Diethyl ether (300 mL) and water (600 mL) were added to the mixture at rt. The organic layer was separated and washed with saturated sodium bicarbonate aqueous solution (2 x 300 mL), brine (300 mL) and dried over sodium sulfate. The aqueous layer was extracted with diethyl ether (2 x 300 mL). The combined organic layers were washed with a saturated NaHC03 aqueous solution (2 x 300 mL), brine (300 mL) and dried over sodium sulfate. The organic extracts were concentrated under reduced pressure. The residue was passed through a column of silica (w-pentane/diethyl ether, 40: 1 ~ 2: 1) to provide a mixture of phenyl propionate, ie/t-butyl 2-methyl-3- oxopentanoate and phenol. 1 M sodium hydroxide aqueous solution (500 mL) was added to a solution of the mixture in diethyl ether (250 mL) and the resulting solution was stirred at rt for 1.5 h. The organic layer was separated and washed with 1 M sodium hydroxide aqueous solution (250 mL), water (250 mL), brine (250 mL) and dried over sodium sulfate. The organic extract was concentrated under reduced pressure to provide iert-butyl 2-methyl-3- oxopentanoate (40.4 g, 87%) as a colorless oil. 1H NMR (CDC13, 600 MHz) δ = 3.42 (q, 2H, J = 7.3 Hz, CH2 of Et), 2.64-2.46 (m, 1H, CH), 1.45 (s, 9H, (CH3)3), 1.29 (d, J = 6.6 Hz, CH3 of Me), 1.08 (t, 3H, J = 1.3 Hz, CH3 of Et). |
| 87% |
Stage #1: tert-butyl propionate With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.25h;
Stage #2: With lithium hexamethyldisilazane In tetrahydrofuran; hexane for 0.0833333h;
Stage #3: phenyl propionate In tetrahydrofuran; hexane at -78℃; for 1h; |
1D.2 tert-Butyl 2-methyl-3-oxopentanoate
A 2.58 M solution of n-butyllithium in hexane (71.0 mL, 183 mmol) and a 2.41 M solution of n-butyllithium in hexane (33.2 mL, 80 mmol) was added dropwise to a solution of hexamethyldisilazane (58.4 mL, 275 mmol) in THF (160 mL) at 0 C and the mixture was stirred at 0 C for 45 min to prepare lithium hexamethyldisilazide (as a hexane and THF solution). A 2.42 M solution of n-butyllithium in hexane (69.0 mL, 167 mmol) and a 2.41 M solution of n-butyllithium in hexane (37.8 mL, 91 mmol) were added dropwise to a solution of diisopropylamine (36.3 mL, 258 mmol) in THF (160 mL) at-78 C. The resulting mixture was warmed to 0 C, stirred for 10 min and recooled to-78 C. A solution of tert-butyl propionate (32.5 g, 250 mmol) in THF (90 mL + 35 mL × 2 wash) was added to the above lithiumdiisopropylamide solution. The resulting mixture was stirred at-78 C for 15 min. A freshly prepared solution of lithium hexamethyldisilazide in hexane and THF (323 mL, 30 mL × 2 wash with THF) was added and then after 5 min a solution of phenyl propionate (39.4 g, 263 mmol) in THF (50 mL + 25 mL × 2 wash) was added to the reaction mixture at-78 C. The resulting mixture was stirred at-78 C. After 1 h, saturated ammonium chloride aqueous solution (150 mL) at-78 C. Diethyl ether (300 mL) and water (600 mL) were added to the mixture at rt. The organic layer was separated and washed with saturated sodium bicarbonate aqueous solution (2 × 300 mL), brine (300 mL) and dried over sodium sulfate. The aqueous layer was extracted with diethyl ether (2 × 300 mL). The combined organic layers were washed with a saturated NaHCO3 aqueous solution (2 × 300 mL), brine (300 mL) and dried over sodium sulfate. The organic extracts were concentrated under reduced pressure. The residue was passed through a column of silica (n-pentane/diethyl ether, 40:1 ~ 2:1) to provide a mixture of phenyl propionate, tert-butyl 2-methyl-3-oxopentanoate and phenol.1 M sodium hydroxide aqueous solution (500 mL) was added to a solution of the mixture in diethyl ether (250 mL) and the resulting solution was stirred at rt for 1.5 h. The organic layer was separated and washed with 1 M sodium hydroxide aqueous solution (250 mL), water (250 mL), brine (250 mL) and dried over sodium sulfate. The organic extract was concentrated under reduced pressure to provide tert-butyl 2-methyl-3-oxopentanoate (40.4 g, 87%) as a colorless oil.1H NMR (CDCl3, 600 MHz) δ = 3.42 (q, 2H, J = 7.3 Hz, CH2 of Et), 2.64-2.46 (m, 1H, CH), 1.45 (s, 9H, (CH3)3), 1.29 (d, J = 6.6 Hz, CH3 of Me), 1.08 (t, 3H, J = 7.3 Hz, CH3 of Et). |
| 86% |
Stage #1: tert-butyl propionate With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.25h; Inert atmosphere;
Stage #2: With lithium hexamethyldisilazane In tetrahydrofuran; hexane at -78℃; Inert atmosphere;
Stage #3: phenyl propionate In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; |
tert-Butyl 2-Methyl-3-oxopentanoate (3)
A solution of n-BuLi in hexanes (2.34 M,103 mL, 242 mmol, 1.025 equiv) was added dropwise via cannula to a solution of i-Pr2NH (34.5 mL, 242 mmol, 1.025 equiv) in THF (104 mL) at -78 °C (dry ice/acetone bath). The resulting colorless solution was stirred at -78 °C for 15 min. A solution of tert-butyl propionate (30.7g, 236 mmol, 1 equiv) in THF (50 mL) was added dropwise via cannula. The resulting pale yellow solution was stirred at -78 °C for 15 min, then the freshly prepared solution of lithium hexamethyldisilazide (vide supra) was added dropwise via cannula. Immediately following completed addition, a solution of phenyl propionate (37.2 g, 248mmol) in THF (50 mL) was added dropwise via cannula. The resulting solution was stirred at -78 °C for 1 h. Sat. aq NH4Cl (200 mL), H2O(400 mL), and Et2O (400 mL) were added sequentially, and the mixture was allowed to warm to 23 °C with stirring. The layers were separated and the aqueous layer was extracted with Et2O (2 × 300 mL). To the combined organic layers was added 2 M aq NaOH (500 mL), and the biphasic mixture was stirred vigorously for 2 h. The layers were separated and the organic layer was washed with H2O (500 mL) followed by brine (500 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure [rotary evaporation, 30 °C (wa-ter bath)/~40 mmHg] to provide 3 as a pale yellow oil; yield: 37.8 g (86%) |
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