ethyl 3-iodopropanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl 3-iodopropanoate (8 g, 35 mmol) and zinc-copper (4.5 g, 70 mmol) in a mixture of benzene (80 mL) and DMA (8 mL) was heated at 60° C. for 4.5 hours under N2. Pd(PPh3)2Cl2 (1.2 g, 1.8 mmol) was added, followed by addition of cyclopropanecarbonyl chloride (3.7 g, 35 mmol). The mixture was stirred at 60° C. for another 30 minutes. The reaction mixture was diluted with ethyl acetate (300 mL), and washed with 1N HCl (50 mL), satd aq NaHCO3 (80 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated to afford the ethyl 4-cyclopropyl-4-oxobutanoate (4.2 g), which was used for next step directly without purification. washed with 1N HCl (50 mL) The organic layer was dried over Na2SO4 concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon gas atmosphere, a mixture of zinc (21.0 g, 321 mmol) and 1,2-dibromoethane (1.40 mL, 16.2 mmol) in tetrahydrofuran (105 mL) was stirred at 80° C. for 20 min. After cooling to room temperature, chlorotrimethylsilane (400 μL, 3.13 mmol) was added at room temperature, and the mixture was stirred for 30 min. A solution of ethyl 3-iodopropanoate (60.0 g, 263 mmol) in tetrahydrofuran (53 mL) was added dropwise to the mixture at room temperature, and the mixture was stirred at 40° C. for 3 hr. A solution of copper(I) cyanide (19.2 g, 214 mmol) and lithium chloride (18.3 g, 432 mmol) in tetrahydrofuran (50 mL) was added dropwise to the mixture at 0° C., and the mixture was stirred for 30 min. This mixture was added dropwise at −78° C. under an argon gas atmosphere to a mixture obtained by stirring a solution of ethyl chlorocarbonate (19.4 mL, 203 mmol) and methyl nicotinate (27.8 g, 203 mmol) in tetrahydrofuran (105 mL) at 0° C. for 30 min, and the mixture was stirred for 12 hr while heating to room temperature. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Xylene (105 mL) and sulfur (20.0 g, 624 mmol) were added to the residue, and the mixture was stirred at 140° C. for 12 hr. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (20.5 g, yield 43%). After cooling to room temperature the mixture was stirred for 30 min the mixture was stirred at 40° C. for 3 hr the mixture was stirred for 30 min This mixture was added dropwise at −78° C. under an argon gas atmosphere to a mixture obtained the mixture was stirred for 12 hr while heating to room temperature the mixture was filtered The filtrate was concentrated under reduced pressure the insoluble material was filtered off The filtrate was extracted with ethyl acetate the extract was dried over anhydrous sodium sulfate The solvent was evaporated under reduced pressure the mixture was stirred at 140° C. for 12 hr After cooling to room temperature the insoluble material was filtered off the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl 4-(acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this added ethyl 3-iodopropanoate (5.54 g) and the mixture was stirred at 50° C. for 8 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1) to give 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate as yellow oil (4.27 g). The mixture was partitioned between AcOEt and water The organic layer was separated washed with brine dried over MgSO4 evaporated in vacuo The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of Zn metal (18 g, 0.27 mol) in DMF (5 mL) was purged with N2. BrCH2CH2Br (2.0 g, 10 mmol) was added, followed by TMSCl (0.92 g, 8.5 mmol). The resulting mixture was stirred at 90° C. for 30 min, and allowed to cool to rt. A solution of compound 57a (50 g, 0.22 mol) in DMF (150 mL) was added, and the resulting mixture was stirred overnight at rt. Pd(PPh3)2Cl2 (7.4 g, 10 mmol) was added, followed by 2,5-dibromopyridine (50 g, 0.21 mol). The resulting mixture was stirred at 68° C. for 2 h. The reaction was quenched by the addition of saturated NaHCO3 solution (300 mL). The resulting solution was extracted with EtOAc (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 57b as a yellow oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C10H12BrNO2: 258.0 (M+H). Found: 258.2. to cool to rt the resulting mixture was stirred overnight at rt The resulting mixture was stirred at 68° C. for 2 h The reaction was quenched by the addition of saturated NaHCO3 solution (300 mL) The resulting solution was extracted with EtOAc (2×100 mL) the combined organic layers were dried over Na2SO4 filtered concentrated under reduced pressure The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v))

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with Zn-Cu couple (200 mg, 3 mmol) solution of ethyl 3-iodopropanoate (510 mg, 2 mmol) in dry toluene (4 mL) and dry N,N-dimethylacetamide (2mL) was added. The mixture was vigorously stirred for 1 hour at room temperature and then heated at gentle reflux for 4.5 hours. After the mixture was cooled to 60° C, a solution of tetrakis(triphenylphosphine)palladium(0)(30 mg, 0.026 mmol) in toluene (2 mL) was added over 1 minute and stirring was continued for 5 minutes at the same temperature. A solution of (45) (309 mg, 1 mmol) in dry toluene (2 mL) was added and the mixture was refluxed for 12 hours. The reaction mixture was allowed to cool to 25° C. and filtered through a Celite pad. The filter cake was washed with ether (50 mL). The filtrate was successively washed with a solution of i N ammonium chloride (10 mL), a solution of saturated sodium hydrogen carbonate (10 mL) and a solution of saturated sodium chloride (10 mL). The aqueous phases were back extracted with ether (30 mL), the combined organic extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (97:03 petroleum ether/EtOAc) afforded (46) (165 mg, 51%) as a colorless oil: Rf 0.44 (95:05 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.19 (m, 4 H), 4.51 (s, 2 H), 4.12 (q, J=7.2 Hz, 2 H), 3.55 (t, J=7.2 Hz, 2 H), 2.94 (t, J=8.1 Hz, 2 H), 2.61 (t, J=8.1 Hz, 2 H), 2.46 (tt, J1 =6.9 Hz, J2 =2.1 Hz, 2 H), 2.13 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.40 (m, 6 H), 1.22 (t, J=7.2 Hz, 3 H), 0.88 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 173.01, 140.87, 138.58, 128.68, 127.75, 81.64, 76.67, 72.99, 69.15, 60.53, 36.02, 31.01, 31.18, 28.81, 22.34, 20.28, 18.85, 14.32, 14.12. ##STR14## was added heated at gentle reflux for 4.5 hours After the mixture was cooled to 60° C stirring was continued for 5 minutes at the same temperature the mixture was refluxed for 12 hours to cool to 25° C. filtered through a Celite pad The filter cake was washed with ether (50 mL) The filtrate was successively washed with a solution of i N ammonium chloride (10 mL) The aqueous phases were back extracted with ether (30 mL) the combined organic extracts were dried (MgSO4) filtered concentrated by rotary evaporation to yield a yellow oil Purification by flash silica gel chromatography (97:03 petroleum ether/EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with Zn-Cu couple (200 mg, 3 mmol) solution of ethyl 3-iodopropanoate (510 mg, 2 mmol) in dry toluene (4 mL) and dry N,N-dimethylacetamide (2mL) was added. The mixture was vigorously stirred for 1 hour at room temperature and then heated at gentle reflux for 4.5 hours. After the mixture was cooled to 60° C, a solution of tetrakis(triphenylphosphine)palladium(0)(30 mg, 0.026 mmol) in toluene (2 mL) was added over 1 minute and stirring was continued for 5 minutes at the same temperature. A solution of (45) (309 mg, 1 mmol) in dry toluene (2 mL) was added and the mixture was refluxed for 12 hours. The reaction mixture was allowed to cool to 25° C. and filtered through a Celite pad. The filter cake was washed with ether (50 mL). The filtrate was successively washed with a solution of i N ammonium chloride (10 mL), a solution of saturated sodium hydrogen carbonate (10 mL) and a solution of saturated sodium chloride (10 mL). The aqueous phases were back extracted with ether (30 mL), the combined organic extracts were dried (MgSO4), filtered, concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (97:03 petroleum ether/EtOAc) afforded (46) (165 mg, 51%) as a colorless oil: Rf 0.44 (95:05 petroleum ether/EtOAc); 1H NMR (CDCl3) δ 7.19 (m, 4 H), 4.51 (s, 2 H), 4.12 (q, J=7.2 Hz, 2 H), 3.55 (t, J=7.2 Hz, 2 H), 2.94 (t, J=8.1 Hz, 2 H), 2.61 (t, J=8.1 Hz, 2 H), 2.46 (tt, J1 =6.9 Hz, J2 =2.1 Hz, 2 H), 2.13 (tt, J1 =7.2 Hz, J2 =2.4 Hz, 2 H), 1.40 (m, 6 H), 1.22 (t, J=7.2 Hz, 3 H), 0.88 (t, J=6.9 Hz, 3 H); 13C NMR (CDCl3) δ 173.01, 140.87, 138.58, 128.68, 127.75, 81.64, 76.67, 72.99, 69.15, 60.53, 36.02, 31.01, 31.18, 28.81, 22.34, 20.28, 18.85, 14.32, 14.12. ##STR14## was added heated at gentle reflux for 4.5 hours After the mixture was cooled to 60° C stirring was continued for 5 minutes at the same temperature the mixture was refluxed for 12 hours to cool to 25° C. filtered through a Celite pad The filter cake was washed with ether (50 mL) The filtrate was successively washed with a solution of i N ammonium chloride (10 mL) The aqueous phases were back extracted with ether (30 mL) the combined organic extracts were dried (MgSO4) filtered concentrated by rotary evaporation to yield a yellow oil Purification by flash silica gel chromatography (97:03 petroleum ether/EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl 4-(acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this added ethyl 3-iodopropanoate (5.54 g) and the mixture was stirred at 50° C. for 8 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1) to give 1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate as yellow oil (4.27 g). The mixture was partitioned between AcOEt and water The organic layer was separated washed with brine dried over MgSO4 evaporated in vacuo The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-3:1)