3-methoxycyclopent-2-en-1-one

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

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

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

Procedure: N-Bromosuccinimide (24.92 g, 0.140 mol) is added, portionwise, over 1 hour to a stirred solution of 3-methoxycyclopent-2-enone (14.95 g, 0.133 mol) in 1,2-dichloroethane (300 ml) at 0° C. in an amber flask. The reaction mixture is stirred at 0° C. for a further 90 minutes and then any remaining solid is removed by filtration. The filtrate is evaporated to dryness under reduced pressure, the resultant solid is dissolved in warm toluene (600 ml) and washed quickly with ice-cold water (2×100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure until approximately 150 ml remains. The residue is cooled with an ice bath and left for 30 minutes. The resultant solid is removed by filtration, washed with hexane (50 ml) and air-dried to give 2-bromo-3-methoxycyclopent-2-enone. any remaining solid is removed by filtration The filtrate is evaporated to dryness under reduced pressure the resultant solid is dissolved in warm toluene (600 ml) washed quickly with ice-cold water (2×100 ml) The organic phase is dried over anhydrous magnesium sulfate filtered the filtrate evaporated under reduced pressure until approximately 150 ml The residue is cooled with an ice bath left for 30 minutes The resultant solid is removed by filtration washed with hexane (50 ml) air-dried

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

Procedure: To a stirred solution of 3-methoxy-cyclopent-2-enone (14.95 g, 0.133 mmol) in 1,2-dichloroethane (300 ml) at 0° C. in an amber flask is added portionwise over one hour N-bromosuccinimide (24.92 g, 140 mmol). The reaction is stirred at 0° C. for a further 90 minutes and then any remaining solid is removed by filtration. The filtrate is evaporated to dryness under reduced pressure, the resultant solid dissolved in warm toluene (600 ml) and washed quickly with water (2×100 ml). The organic phase is evaporated under reduced pressure until a precipitate appears. The residue is cooled overnight in a fridge. The resultant solid is removed by filtration, washed with hexane (50 ml) and air-dried to give 15.2 g of 2-bromo-3-methoxy-cyclopent-2-enone as a white crystalline solid. any remaining solid is removed by filtration The filtrate is evaporated to dryness under reduced pressure the resultant solid dissolved in warm toluene (600 ml) washed quickly with water (2×100 ml) The organic phase is evaporated under reduced pressure until a precipitate The residue is cooled overnight in a fridge The resultant solid is removed by filtration washed with hexane (50 ml) air-dried

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

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

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromonapthalene (8.03 g, 38.8 mmol) in anhydrous tetrahydrofuran (200 mL) at −78° C. was treated with a solution of n-butyllithium (1.6 M in hexane; 26.9 mL, 43.0 mmol, 1.1 eq.) such that the reaction temperature remained at −78° C. After 15 min, a solution of 3-methoxy-2-cyclopenten-1-one (5.0 g, 44.6 mmol, 1.1 eq.) in anhydrous tetrahydrofuran (50 mL) was added such that the reaction temperature remained below −78° C. The reaction was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl (100 mL) and concentrated in vacuo to remove tetrahydrofuran. A solution of 1N HCl (100 mL) was added, stirred for 30 min and extracted with ethylacetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 mL), brine (100 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 3:7 ethyl acetate/petrol as the eluting solvent to afford (2.77 g, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.63-2.66 (2H, m, CH2), 3.17-3.20 (2H, m, CH2), 6.70 (1H, t, J 1.6 Hz, CH), 7.53-7.59 (2H, m, ArH), 7.75 (1H, dd, J 1.6, 8.5 Hz, ArH), 7.85-7.93 (3H, m, ArH), 8.12 (1H, s, ArH). remained at −78° C remained below −78° C quenched with a solution of 1N HCl (100 mL) concentrated in vacuo to remove tetrahydrofuran A solution of 1N HCl (100 mL) was added extracted with ethylacetate (3×100 mL) The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (100 mL), brine (100 mL) dried over magnesium sulphate filtered concentrated in vacuo The residue was purified by silica gel chromatography to afford (2.77 g, 28%) as a white solid

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-iodonapthalene (10.00 g, 39.36 mmol) in tetrahydrofuran (300 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes; 17.49 mL, 43.73 mmol, 1.1 eq.) so that the reaction temperature remained ≦−78° C. The reaction mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 3-methoxy-2-cyclopenten-1-one (5.10 g, 45.48 mmol, 1.16 eq.) in tetrahydrofuran (50 mL) so that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over a 2 h period and the reaction mixture was quenched with a solution of 1N HCl and concentrated in vacuo to remove the organics. A solution of 1N HCl was added and the reaction mixture was stirred for a further 0.5 h and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) followed by brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford a yellow oil. The crude oil was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 20%:80%) to afford the desired compound as an off-white solid (4.01 g, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 2.68 (2H, dt, J 2, 4.8 Hz, CH2), 3.16 (2H, td, J 2.4, 4.8 Hz, CH2), 6.51 (1H, t, J 1.6 Hz, CH), 7.54-7.60 (4H, m, ArH), 7.93-8.01 (2H, m, ArH), 8.10-8.18 (1H, m, ArH). remained ≦−78° C remained ≦−78° C the reaction mixture was quenched with a solution of 1N HCl concentrated in vacuo to remove the organics A solution of 1N HCl was added the reaction mixture was stirred for a further 0.5 h extracted with ethyl acetate (3×100 mL) washed with saturated aqueous sodium bicarbonate (100 mL) dried over magnesium sulphate concentrated in vacuo to afford a yellow oil The crude oil was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 20%:80%)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-iodonapthalene (10.00 g, 39.36 mmol) in tetrahydrofuran (300 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes; 17.49 mL, 43.73 mmol, 1.1 eq.) so that the reaction temperature remained ≦−78° C. The reaction mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 3-methoxy-2-cyclopenten-1-one (5.10 g, 45.48 mmol, 1.16 eq.) in tetrahydrofuran (50 mL) so that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over a 2 h period and the reaction mixture was quenched with a solution of 1N HCl and concentrated in vacuo to remove the organics. A solution of 1N HCl was added and the reaction mixture was stirred for a further 0.5 h and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) followed by brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford a yellow oil. The crude oil was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 20%:80%) to afford the desired compound as an off-white solid (4.01 g, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 2.68 (2H, dt, J 2, 4.8 Hz, CH2), 3.16 (2H, td, J 2.4, 4.8 Hz, CH2), 6.51 (1H, t, J 1.6 Hz, CH), 7.54-7.60 (4H, m, ArH), 7.93-8.01 (2H, m, ArH), 8.10-8.18 (1H, m, ArH). remained ≦−78° C remained ≦−78° C the reaction mixture was quenched with a solution of 1N HCl concentrated in vacuo to remove the organics A solution of 1N HCl was added the reaction mixture was stirred for a further 0.5 h extracted with ethyl acetate (3×100 mL) washed with saturated aqueous sodium bicarbonate (100 mL) dried over magnesium sulphate concentrated in vacuo to afford a yellow oil The crude oil was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 20%:80%)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1,2-dichloro-4-iodobenzene (1.0 g, 3.66 mmol) in THF (50 mL) at −78° C. was treated with a solution of n-butyllithium (2.5 M in hexanes; 1.5 mL, 3.8 mmol) such that the reaction temperature remained ≦−78° C. After 15 min, a solution of 3-methoxy-2-cyclopenten-1-one (0.452 g, 3.96 mmol) in THF (20 mL) was added such that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl and concentrated in vacuo to remove THF. A solution of 1N HCl (5 mL) was added, the solution was stirred for 30 min and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc/Heptanes as the eluting solvent to afford 0.3 g of target compound as a white powder (Yield 36%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.58-2.62 (m, 2 H) 2.97-3.03 (m, 2 H) 6.56 (t, 1 H) 7.45-7.55 (m, 2 H) 7.71 (d, 1 H). remained ≦−78° C remained ≦−78° C quenched with a solution of 1N HCl concentrated in vacuo to remove THF A solution of 1N HCl (5 mL) was added extracted with EtOAc (2×) The combined organic extracts were washed with saturated aqueous NaHCO3, brine dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel chromatography

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-iodotoluene (10 g, 45 mmol) in THF (300 mL) at −78° C. was treated with a solution of n-butyllithium (2.5 M in hexanes; 20 mL, 50 mmol) such that the reaction temperature remained ≦−78° C. After 15 minutes, a solution of 3-methoxy-2-cyclopenten-1-one (5.78 g, 52 mmol) in THF (50 mL) was added such that the reaction temperature remained ≦−78° C. The reaction mixture was warmed to −20° C. over 2 h, quenched with a solution of 1N HCl and concentrated in vacuo to remove THF. A solution of 1N HCl (40 mL) was added, the solution was stirred for 30 min and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using heptane/EtOAc as the eluting solvent to afford 4.92 g of 3-p-tolyl-cyclopent-2-enone as a white powder (Yield 63.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.42 (s, 3 H) 2.59 (ddd, J=4.83, 2.64, 2.49 Hz, 2 H) 3.05 (td, J=4.98, 1.76 Hz, 2 H) 6.55 (t, J=1.66 Hz, 1 H) 7.27 (d, J=8.00 Hz, 2 H) 7.57 (dt, J=8.30, 1.90 Hz, 2 H). remained ≦−78° C remained ≦−78° C quenched with a solution of 1N HCl concentrated in vacuo to remove THF A solution of 1N HCl (40 mL) was added extracted with EtOAc (3×) The combined organic extracts were washed with saturated aqueous NaHCO3, brine dried over MgSO4 filtered concentrated in vacuo The residue was purified by silica gel chromatography

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

Procedure: A mixture of Example 7A (500 mg, 4.46 mmol) and N-bromosuccinimide (794 mg, 4.46 mmol) in dichloromethane (5 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated in vacuo. The residue was purified on a silica column (dichloromethane/methanol=200:1, v/v) to afford the title compound (650 mg, 3.40 mmol, 76% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.12 (s, 3H), 2.79-2.82 (m, 2H), 2.62-2.65 (m, 2H); LC/MS (ESI) m/z 191 (M+H)+. The mixture was concentrated in vacuo The residue was purified on a silica column (dichloromethane/methanol=200:1