N-methoxy-N-methylcyclopent-3-ene-1-carboxamide

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: Bromo-2,4,6-trimethylbenzene (16.9 g, 85 mmol) was stirred in anhydrous THF (340 mL) at −78° C. under nitrogen and treated with t-BuLi (100 mL of 1.7 M soln. in pentane, 170 mmol) dropwise via an addition funnel over 30 min. A yellow slurry forms and is stirred 1 h. To this was added 2-methoxypyridine (8.45 g, 77.3 mmol) in anhydrous THF (10 mL) over 5 min. The mixture was allowed to warm to 0° C. and stirred for 1 h, then at ambient temperature for 1 h, then recooled to −78° C. and treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (12.4 g, 80 mmol) in anhydrous THF (20 mL) over 5 min. The resulting mixture was stirred 18 h (the bath evaporated and the mixture achieved ambient temperatures). The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and stirred 20 min. The mixture was extracted with Et2O (3×100 mL). The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4, filtered and concentrated to an oil (26 g). Purification by chromatography on silica gel eluting first with hexane to remove mesitylene followed by 10% then 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude). (TLC 10% Et2O/hexanes Rf 0.36); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (m, 1H), 6.97 (m, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 4.17, (m, 1H), 2.67 (m, 4H); GCMS m/z 203 (M)+. stirred for 1 h at ambient temperature for 1 h recooled to −78° C. The resulting mixture was stirred 18 h (the bath evaporated The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) stirred 20 min The mixture was extracted with Et2O (3×100 mL) The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4 filtered concentrated to an oil (26 g) Purification by chromatography on silica gel eluting first with hexane to remove mesitylene 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude)

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

Procedure: Bromo-2,4,6-trimethylbenzene (16.9 g, 85 mmol) was stirred in anhydrous THF (340 mL) at −78° C. under nitrogen and treated with t-BuLi (100 mL of 1.7 M soln. in pentane, 170 mmol) dropwise via an addition funnel over 30 min. A yellow slurry forms and is stirred 1 h. To this was added 2-methoxypyridine (8.45 g, 77.3 mmol) in anhydrous THF (10 mL) over 5 min. The mixture was allowed to warm to 0° C. and stirred for 1 h, then at ambient temperature for 1 h, then recooled to −78° C. and treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (12.4 g, 80 mmol) in anhydrous THF (20 mL) over 5 min. The resulting mixture was stirred 18 h (the bath evaporated and the mixture achieved ambient temperatures). The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and stirred 20 min. The mixture was extracted with Et2O (3×100 mL). The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4, filtered and concentrated to an oil (26 g). Purification by chromatography on silica gel eluting first with hexane to remove mesitylene followed by 10% then 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude). (TLC 10% Et2O/hexanes Rf 0.36); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (m, 1H), 6.97 (m, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 4.17, (m, 1H), 2.67 (m, 4H); GCMS m/z 203 (M)+. stirred for 1 h at ambient temperature for 1 h recooled to −78° C. The resulting mixture was stirred 18 h (the bath evaporated The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) stirred 20 min The mixture was extracted with Et2O (3×100 mL) The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4 filtered concentrated to an oil (26 g) Purification by chromatography on silica gel eluting first with hexane to remove mesitylene 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude)

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

Procedure: 3-Fluoromethoxybenzene (15.8 g, 125 mmol) was stirred at -78° C. in anh. THF (100 mL) and treated with n-BuLi (50 mL, 2.5M hexanes soln., 125 mmol) over 5 min. After stirring below −70° C. for 4 hours, the mixture was treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (18.4 g, 119 mmol) dropwise over ˜¼ hour. The mixture was stirred below −70° C. for 1 hour, and then allowed to warm to ambient temperature over ˜1 hour. The mixture was poured into 1N aq. HCl soln. (200 mL) and shaken. The layers were separated and the aq. layer extracted with EtOAc (3×100 mL). The organic layer was washed with H2O (50 mL), sat. aq. NaHCK soln. (100 mL), and brine (50 mL), dried (Na2SO4), filtered through a Silica plug and concentrated to an oil (21.0 g, 76%). (TLC 30%EtOAc/hexanes Rf 0.43). GCMS m/e 220 (M+). This material was converted to the title compound by the methods described in Example 2C-G and Example 1G. (TLC 10%MeOH/CH2Cl2 (NH3) Rf 0.20). 1H NMR (CD3OD) δ7.24 (m. 1H), 7.01 (m, 2H), 3.36 (d, J=13.0 Hz, 1H), 3.33-3.10 (m, 5H), 2.90 (d, J=18.5 Hz, 1H), 2.60 (m, 1H), 2.13 (AB d, J=13.0 Hz, 1H), 1.97 (AB d, J=13.0 Hz, 1H). mp 240-241° C. The mixture was stirred below −70° C. for 1 hour (200 mL) and shaken The layers were separated the aq. layer extracted with EtOAc (3×100 mL) The organic layer was washed with H2O (50 mL), sat. aq. NaHCK soln (100 mL), and brine (50 mL), dried (Na2SO4) filtered through a Silica plug concentrated to an oil (21.0 g, 76%)

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

Procedure: Bromo-2,4,6-trimethylbenzene (16.9 g, 85 mmol) was stirred in anhydrous THF (340 mL) at −78° C. under nitrogen and treated with t-BuLi (100 mL of 1.7 M soln. in pentane, 170 mmol) dropwise via an addition funnel over 30 min. A yellow slurry forms and is stirred 1 h. To this was added 2-methoxypyridine (8.45 g, 77.3 mmol) in anhydrous THF (10 mL) over 5 min. The mixture was allowed to warm to 0° C. and stirred for 1 h, then at ambient temperature for 1 h, then recooled to −78° C. and treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (12.4 g, 80 mmol) in anhydrous THF (20 mL) over 5 min. The resulting mixture was stirred 18 h (the bath evaporated and the mixture achieved ambient temperatures). The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and stirred 20 min. The mixture was extracted with Et2O (3×100 mL). The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4, filtered and concentrated to an oil (26 g). Purification by chromatography on silica gel eluting first with hexane to remove mesitylene followed by 10% then 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude). (TLC 10% Et2O/hexanes Rf 0.36); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (m, 1H), 6.97 (m, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 4.17, (m, 1H), 2.67 (m, 4H); GCMS m/z 203 (M)+. stirred for 1 h at ambient temperature for 1 h recooled to −78° C. The resulting mixture was stirred 18 h (the bath evaporated The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) stirred 20 min The mixture was extracted with Et2O (3×100 mL) The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4 filtered concentrated to an oil (26 g) Purification by chromatography on silica gel eluting first with hexane to remove mesitylene 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude)

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

Procedure: 3-Fluoromethoxybenzene (15.8 g, 125 mmol) was stirred at −78° C. in anh. THF (100 mL) and treated with n-BuLi (50 mL, 2.5M hexanes soln., 125 mmol) over 5 min. After stirring below −70° C. for 4 hours, the mixture was treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (18.4 g, 119 mmol) dropwise over ˜¼ hour. The mixture was stirred below −70° C. for 1 hour, and then allowed to warm to ambient temperature over ˜1 hour. The mixture was poured into 1N aq. HCl soln. (200 mL) and shaken. The layers were separated and the aq. layer extracted with EtOAc (3×100 mL). The organic layer was washed with H2O (50 mL), sat. aq. NaHCO3 soln. (100 mL), and brine (50 mL), dried (Na2SO4), filtered through a Silica plug and concentrated to an oil (21.0 g, 76%). (TLC 30% EtOAc/hexanes Rf 0.43). GCMS m/e 220 (M+). This material was converted to the title compound by the methods described in Example 2C-G and Example 1G. (TLC 10% MeOH/CH2Cl2 (NH3) Rf 0.20). 1H NMR (CD3OD) δ 7.24 (m, 1H), 7.01 (m, 2H), 3.36 (d, J=13.0 Hz, 1H), 3.33-3.10 (m, 5H), 2.90 (d, J=18.5 Hz, 1H), 2.60 (m, 1H), 2.13 (AB d, J=13.0 Hz, 1 H), 1.97 (AB d, J=13.0 Hz, 1H). mp 240-241° C. The mixture was stirred below −70° C. for 1 hour (200 mL) and shaken The layers were separated the aq. layer extracted with EtOAc (3×100 mL) The organic layer was washed with H2O (50 mL), sat. aq. NaHCO3 soln (100 mL), and brine (50 mL), dried (Na2SO4) filtered through a Silica plug concentrated to an oil (21.0 g, 76%)

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

Procedure: 3-Fluoromethoxybenzene (15.8 g, 125 mmol) was stirred at −78° C. in anh. THF (100 mL) and treated with n-BuLi (50 mL, 2.5M hexanes soln., 125 mmol) over 5 min. After stirring below −70° C. for 4 hours, the mixture was treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (18.4 g, 119 mmol) dropwise over ˜¼ hour. The mixture was stirred below −70° C. for 1 hour, and then allowed to warm to ambient temperature over ˜1 hour. The mixture was poured into 1N aq. HCl soln. (200 mL) and shaken. The layers were separated and the aq. layer extracted with EtOAc (3×100 mL). The organic layer was washed with H2O (50 mL), sat. aq. NaHCO3 soln. (100 mL), and brine (50 mL), dried (Na2SO4), filtered through a Silica plug and concentrated to an oil (21.0 g, 76%). (TLC 30% EtOAc/hexanes Rf 0.43). GCMS m/e 220 (M+). This material was converted to the title compound by the methods described in Example 2C-G and Example 1G. (TLC 10% MeOH/CH2Cl2 (NH3) Rf 0.20). 1H NMR (CD3OD) δ 7.24 (m, 1H), 7.01 (m, 2H), 3.36 (d, J=13.0 Hz, 1H), 3.33-3.10 (m, 5H), 2.90 (d, J=18.5 Hz, 1H), 2.60 (m, 1H), 2.13 (AB d, J=13.0 Hz, 1 H), 1.97 (AB d, J=13.0 Hz, 1H). mp 240-241° C. The mixture was stirred below −70° C. for 1 hour (200 mL) and shaken The layers were separated the aq. layer extracted with EtOAc (3×100 mL) The organic layer was washed with H2O (50 mL), sat. aq. NaHCO3 soln (100 mL), and brine (50 mL), dried (Na2SO4) filtered through a Silica plug concentrated to an oil (21.0 g, 76%)

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

Procedure: To a solution of cyclopent-3-ene-1-carboxylic acid (80.0 g, 0.71 mol) in dichloromethane (300 ml) was added 1,1′-carbonyldiimidazole (127.5 g, 0.78 mol) slowly and the reaction mixture was stirred at room temperature for 1 h. N,O-dimethylhydroxylamine (76.7 g, 0.78 mol) was added and stirred for 18 h at room temperature. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (100 ml). The organic extracts were washed with hydrochloric acid (1N, 2×200 ml) and then with brine before filtering through cotton wool, drying and concentrating. The product was purified by flash chromatography using silica gel eluting with dichloromethane to give the title compound (116.78 g, 95%). stirred for 18 h at room temperature extracted with dichloromethane (100 ml) The organic extracts were washed with hydrochloric acid (1N, 2×200 ml) with brine before filtering through cotton wool drying concentrating The product was purified by flash chromatography

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

Procedure: 3- Fluoromethoxybenzene (15.8 g, 125 mmol) was stirred at −78° C. in anh. THF (100 mL) and treated with n-BuLi (50 mL, 2.5M hexanes soln., 125 mmol) over 5 min. After stirring below −70° C. for 4 hours, the mixture was treated with cyciopent-3-enecarboxylic acid methoxy-methyl-amid (18.4 g, 119 mmol) dropwise over ˜1/4 hour. The mixture was stirred below −70° C. for 1 hour, and then allowed to warm to ambient temperature over ˜1 hour. The mixture was poured into 1N aq. HCl soin. (200 mL) and shaken. The layers were separated and the aq. layer extracted with EtOAc (3×100 mL). The organic layer was washed with H2O (50 mL) sat. aq. NaHCO3 soin. (100 mL), and brine (50 mL), dried (Na2SO4), filtered through a Silica plug and concentrated to an oil (21.0 g, 76%). (TLC 30%EtOAc/hexanes Rf 0.43). GCMS m/e 220 (M+). This material was converted to the title compound by the methods described in Example 2C-G and Example 1G. (TLC 10%MeOH/CH2Cl2 (NH3) Rf 0.20). 1H NMR (CD3OD) δ 7.24 (m, 1H), 7.01 (m, 2H), 3.38 (d, J=13.0 Hz, 1H), 3.33-3.10 (m, 5H), 2.90 (d, J=18.5 Hz, 1H), 2.60 (m, 1H), 2.13 (AB d, J=13.0 Hz, 1H), 1.97 (AB d, J=13.0 Hz, 1H), mp 240-241° C.). The mixture was stirred below −70° C. for 1 hour (200 mL) and shaken The layers were separated the aq. layer extracted with EtOAc (3×100 mL) The organic layer was washed with H2O (50 mL) sat. aq. NaHCO3 soin (100 mL), and brine (50 mL), dried (Na2SO4) filtered through a Silica plug concentrated to an oil (21.0 g, 76%)

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

Procedure: 3-Fluoromethoxybenzene (15.8 g, 125 mmol) was stirred at -78° C. in anh. THF (100 mL) and treated with n-BuLi (50 mL, 2.5M hexanes soln., 125 mmol) over 5 min. After stirring below −70° C. for 4 hours, the mixture was treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (18.4 g, 119 mmol) dropwise over ˜¼ hour. The mixture was stirred below −70° C. for 1 hour, and then allowed to warm to ambient temperature over ˜1 hour. The mixture was poured into 1N aq. HCl soln. (200 mL) and shaken. The layers were separated and the aq. layer extracted with EtOAc (3×100 mL). The organic layer was washed with H2O (50 mL), sat. aq. NaHCK soln. (100 mL), and brine (50 mL), dried (Na2SO4), filtered through a Silica plug and concentrated to an oil (21.0 g, 76%). (TLC 30%EtOAc/hexanes Rf 0.43). GCMS m/e 220 (M+). This material was converted to the title compound by the methods described in Example 2C-G and Example 1G. (TLC 10%MeOH/CH2Cl2 (NH3) Rf 0.20). 1H NMR (CD3OD) δ7.24 (m. 1H), 7.01 (m, 2H), 3.36 (d, J=13.0 Hz, 1H), 3.33-3.10 (m, 5H), 2.90 (d, J=18.5 Hz, 1H), 2.60 (m, 1H), 2.13 (AB d, J=13.0 Hz, 1H), 1.97 (AB d, J=13.0 Hz, 1H). mp 240-241° C. The mixture was stirred below −70° C. for 1 hour (200 mL) and shaken The layers were separated the aq. layer extracted with EtOAc (3×100 mL) The organic layer was washed with H2O (50 mL), sat. aq. NaHCK soln (100 mL), and brine (50 mL), dried (Na2SO4) filtered through a Silica plug concentrated to an oil (21.0 g, 76%)

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

Procedure: Bromo-2,4,6-trimethylbenzene (16.9 g, 85 mmol) was stirred in anhydrous THF (340 mL) at −78° C. under nitrogen and treated with t-BuLi (100 mL of 1.7 M soln. in pentane, 170 mmol) dropwise via an addition funnel over 30 min. A yellow slurry forms and is stirred 1 h. To this was added 2-methoxypyridine (8.45 g, 77.3 mmol) in anhydrous THF (10 mL) over 5 min. The mixture was allowed to warm to 0° C. and stirred for 1 h, then at ambient temperature for 1 h, then recooled to −78° C. and treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (12.4 g, 80 mmol) in anhydrous THF (20 mL) over 5 min. The resulting mixture was stirred 18 h (the bath evaporated and the mixture achieved ambient temperatures). The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and stirred 20 min. The mixture was extracted with Et2O (3×100 mL). The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4, filtered and concentrated to an oil (26 g). Purification by chromatography on silica gel eluting first with hexane to remove mesitylene followed by 10% then 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude). (TLC 10% Et2O/hexanes Rf 0.36); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (m, 1H), 6.97 (m, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 4.17, (m, 1H), 2.67 (m, 4H); GCMS m/z 203 (M)+. stirred for 1 h at ambient temperature for 1 h recooled to −78° C. The resulting mixture was stirred 18 h (the bath evaporated The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) stirred 20 min The mixture was extracted with Et2O (3×100 mL) The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4 filtered concentrated to an oil (26 g) Purification by chromatography on silica gel eluting first with hexane to remove mesitylene 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude)