N-methoxy-N-methylpropanamide

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 solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane is added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath is removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature has cooled to −60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF iss added dropwise. The reaction mixture is stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It is then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer is separated, washing with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material is dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture is concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate is separated, washed with brine, dried (MgSO4) and concentrated. The residue is chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole. The bath is removed to rise to 0° C. added dropwise the cooling bath removed stirred an additional 18 hours It is then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl The organic layer is separated washing with water, brine dried over MgSO4 concentrated at reduced pressure

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

Procedure: A solution of 140 mL (0.18 mol) of 1.3 M sec-butyl lithium in cyclohexane is added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath is removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature is cooled to −60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF is added dropwise. The reaction mixture is stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It is then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer is separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material is dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture is concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate is separated, washed with brine, dried (MgSO4) and concentrated. The residue is chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole. The bath is removed to rise to 0° C. the cooling bath removed stirred an additional 18 hours It is then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl The organic layer is separated washed with water, brine dried over MgSO4 concentrated at reduced pressure

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

Procedure: A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to -60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1- [2- (tert-butoxycarbonylamino) -6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole. The bath was removed to rise to 0° C. the cooling bath removed stirred an additional 18 hours It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl The organic layer was separated washed with water, brine dried over MgSO4 concentrated at reduced pressure

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

Procedure: A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature had cooled to −60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of a crude of 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9 g of 2-ethyl-4-methoxy-1H-indole. The bath was removed to rise to 0° C. the cooling bath removed stirred an additional 18 hours It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl The organic layer was separated washed with water, brine dried over MgSO4 concentrated at reduced pressure

Conditions: temp:-71.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cool a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (2.00 g, 8.367 mmol) and THF (17 mL) to −71° C., and then add n-butyl lithium (2.5 M in hexanes, 9.204 mmol, 3.681 mL) over 5 minutes. Stir the mixture for 15 minutes at −71° C. Add N-methoxy-N-methylpropanamide (0.980 g, 8.367 mmol) to the mixture drop-wise over 3-4 minutes keeping temperature below −65° C. Continue to stir the solution at −71° C. for 15-20 minutes; then warm the solution to room temperature. Stir at room temperature for 40 minutes. Quench the reaction with a saturated ammonium chloride aqueous solution. Extract the aqueous layer with Et2O. Wash the combined organic extracts with water and brine. Dry the mixture over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (40 g RediSep® column) eluting with a gradient of 0-40% DCM/pentane to give the title compound as a colorless oil (1.490 g, 82% yield). 1H NMR (399.80 MHz, d6-DMSO) δ 7.84 (d, J=7.8 Hz, 1H), 7.64-7.61 (m, 2H), 2.93 (q, J=7.1 Hz, 2H), 2.39 (s, 3H), 1.03 (t, J=7.2 Hz, 3H). temperature below −65° C to stir the solution at −71° C. for 15-20 minutes then warm the solution to room temperature Stir at room temperature for 40 minutes Quench the reaction with a saturated ammonium chloride aqueous solution Extract the aqueous layer with Et2O Wash the combined organic extracts with water and brine Dry the mixture over sodium sulfate filter collect the filtrate and concentrate the filtrate under reduced pressure Purify the residue by flash chromatography (40 g RediSep® column) eluting with a gradient of 0-40% DCM/pentane

Conditions: temp:-71.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cool a solution of 1-bromo-2-methyl-4-(trifluoromethyl)benzene (2.00 g, 8.367 mmol) and THF (17 mL) to −71° C., and then add n-butyl lithium (2.5 M in hexanes, 9.204 mmol, 3.681 mL) over 5 minutes. Stir the mixture for 15 minutes at −71° C. Add N-methoxy-N-methylpropanamide (0.980 g, 8.367 mmol) to the mixture drop-wise over 3-4 minutes keeping temperature below −65° C. Continue to stir the solution at −71° C. for 15-20 minutes; then warm the solution to room temperature. Stir at room temperature for 40 minutes. Quench the reaction with a saturated ammonium chloride aqueous solution. Extract the aqueous layer with Et2O. Wash the combined organic extracts with water and brine. Dry the mixture over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (40 g RediSep® column) eluting with a gradient of 0-40% DCM/pentane to give the title compound as a colorless oil (1.490 g, 82% yield). 1H NMR (399.80 MHz, d6-DMSO) δ 7.84 (d, J=7.8 Hz, 1H), 7.64-7.61 (m, 2H), 2.93 (q, J=7.1 Hz, 2H), 2.39 (s, 3H), 1.03 (t, J=7.2 Hz, 3H). temperature below −65° C to stir the solution at −71° C. for 15-20 minutes then warm the solution to room temperature Stir at room temperature for 40 minutes Quench the reaction with a saturated ammonium chloride aqueous solution Extract the aqueous layer with Et2O Wash the combined organic extracts with water and brine Dry the mixture over sodium sulfate filter collect the filtrate and concentrate the filtrate under reduced pressure Purify the residue by flash chromatography (40 g RediSep® column) eluting with a gradient of 0-40% DCM/pentane

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

Procedure: A solution of 3,4-dibromothiophene (6.0 g, 24.8 mmol) in 10 mL of ether was cooled to -78° C. and trated with n-butyllithium (9.92 mL, 2.5M solution in hexanes, 24.8 mmol). While holding the temperature at -78° C., the reaction was stirred for 15 minutes, then 2.9 g (24.8 mmol) of N-methyl-N-methoxypropionamide was added and the reaction was stirred for 1 hour. The reaction was quenched with satd NH4Cl, and the mixture was diluted with ether. The ether layer was separated, washed with water and brine, dried over MgSO4 and concentrated. The residue was triturated with hexanes, and the mixture was filtered. The solvent was removed to give 2.08 g of a tan solid. MS 236, 238 (M+NH4)+. NMR (CDCl3) δ:7.99 (d, J=3 Hz, 1H), 7.32 (d, J=3 Hz, 1H), 2.98 (q, J=7 Hz, 2H), 1.21 (t, J=7 Hz, 3H). at -78° C. the reaction was stirred for 1 hour The reaction was quenched with satd NH4Cl the mixture was diluted with ether The ether layer was separated washed with water and brine dried over MgSO4 concentrated The residue was triturated with hexanes the mixture was filtered The solvent was removed