| 55% |
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 2 h; Inert atmosphere
Stage #2: at -78℃; for 1.75 h; Inert atmosphere |
Step 2: Preparation of ethyl 8-formyl-l,4-dioxaspiro[4.5]decane-8-carboxylate. To a -78 °C solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (32.31 g, 151 mmol) in THF (250 mL) was added a solution of 2M lithium diisopropylamide (98 mL, 196 mmol) in THF via a cannula over 5 mins. The resulting brown solution was stirred at -78 °C. After lh, the cold bath was replaced with an ice bath and the reaction mixture was stirred at 0 °C for lh. The reaction mixture was again chilled to -78 °C and treated with a solution of ethyl formate (18.65 mL, 226 mmol) in THF (40 mL) added dropwise over 45 min. The resulting light brown reaction mixture was stirred at -78 °C for lh. The cold bath was removed and to the mixture was added dropwise saturated aqueous NH4C1 (250 mL) and the mixture stirred at ambient temperature for 30 min. The resulting yellow mixture was extracted with EtO Ac (3 x 300 mL). The combined organic phase was washed with 0.5N HC1 (300 mL), then with brine, dried over MgS04, filtered and concentrated to a brown viscous oil. The crude material was purified by flash column chromatography over silica gel (750 g silica, step elution 9: 1 hexanes/EtOAc and 5: 1 hexanes/EtOAc) to provide recovered starting material, ethyl l,4-dioxaspiro[4.5]decane- 8-carboxylate (8.6 g, 40.1 mmol, 26.6 percent yield) and the desired product, ethyl 8-formyl- l,4-dioxaspiro[4.5]decane-8-carboxylate (20.1 g, 83 mmol, 55.0 percent yield), both as viscous yellow oils. NMR (400MHz, CHLOROFORM-d) δ 9.50 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.94 - 3.86 (m, 4H), 2.24 - 2.09 (m, 2H), 2.01 (ddd, J=13.5, 8.3, 5.1 Hz, 2H), 1.75 - 1.48 (m, 4H), 1.23 (t, J=7.2 Hz, 3H). |
| 55% |
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 2 h;
Stage #2: at -78℃; for 1.45 h; |
To a -78 °C solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (32.31 g, 151 mmol) in THF (250 mL) was added a solution of 2M lithium diisopropylamide (98 mL, 196 mmol) in THF via a cannula over 5 mins. The resulting brown solution was stirred at -78 °C. After 1h, the cold bath was replaced with an ice bath and the reaction mixture was stirred at 0 °C for 1h. The reaction mixture was again chilled to -78 °C and treated with a solution of ethyl formate (18.65 mL, 226 mmol) in THF (40mL) added dropwise over 45 min. The resulting light brown reaction mixture was stirred at -78 °C for 1h. The cold bath was removed and to the mixture was added dropwise saturated aqueous NH4Cl (250mL) and the mixture stirred at ambient temperature for 30 min. The resulting yellow mixture was extracted with EtOAc (3 x 300 mL). The combined organic phase was washed with 0.5N HCl (300mL), then with brine, dried over MgSO4, filtered and concentrated to a brown viscous oil. The crude material was purified by flash column chromatography over silica gel (750 g silica, step elution 9:1 hexanes/EtOAc and 5:1 hexanes/EtOAc) to provide recovered starting material, ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (8.6 g, 40.1 mmol, 26.6percent yield) and the desired product, ethyl 8-formyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (20.1 g, 83 mmol, 55.0 percent yield), both as viscous yellow oils. H1 NMR (400 MHz, CHLOROFORM-d) δ 9.50(s, 1H), 4.17(q, J=7.2 Hz, 2H), 3.94-3.86(m, 4H), 2.24-2.09(m, 2H), 2.01(ddd, J=13.5, 8.3, 5.1 Hz, 2H), 1.75-1.48(m, 4H), 1.23(t, J=7.2 Hz, 3H). |
| 39% |
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2.5 h; Cooling with ice
Stage #2: at -78℃; for 2 h; Molecular sieve |
To a solution of ethyl 1,4-dioxaspiro[4.5jdecane-8-carboxylate (21 g, 98 mmol) in THF(150 mL) at -78 °C was added 2M LDA (64 mL, 127 mmol) dropwise. The resultingsolution was stirred at -78 °C for 1 h, then in an ice bath for 1.5 h. The reaction mixturewas chilled back to -78 °C and molecular sieves were added. Dried ethyl formate (12 mL,147 mmol) was added dropwise slowly over 1 h. The reaction mixture was stirred at -78°C for 1 h. The cold bath was removed and the reaction was quenched with a saturatedsolution of NH4C1 in 0.5 N HC1 (250 mL) dropwise. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with saturated solution of NH4C1 in 0.5 N HC1 (200 mL), brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The cmde product was purified by silica gel column eluted with 0-20 percent ethyl acetate I hexanes to give the desired product as an oil (9.3 g, 39 percent). ‘H NMR (400MHz,CHLOROFORM-d) ö 9.54 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.98 - 3.90 (m, 4H), 2.25 -2.16 (m, 2H), 2.10 - 2.01 (m, 2H), 1.74 - 1.60 (m, 4H), 1.27 (t, J=7.2 Hz, 3H). |
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