3,5-dichloro-N-Methoxy-N-MethylbenzaMide

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:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-methoxy-1-ethynyl benzene (0.57 g, 4.27 mmol) in 20 mL of anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (3.2 mL, 5.12 mmol). After 5 minutes a solution of 3,5-dichloro-N-methoxy-N-methylbenzamide (1.0 g, 4.27 mmol) in THF (10 mL) was added to the reaction. The reaction was slowly warmed to −40° C. over 30 minutes and then quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:10 ethyl acetate-hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.09(d, J=2.0 Hz, 2H), 7.7(d, J=7.1 Hz, 2H), 7.64(t, J=1.8 Hz, 1H), 7.0(d, J=8.7 Hz, 1H), 3.91(s, 3H). quenched with saturated NH4Cl solution The resulting bi-phasic mixture was extracted with EtOAc (3×) The organic layer was washed with brine dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by flash chromatography

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

Procedure: To the product from step A (5.42 g, 23.2 mmol) in 100 mL of tetrahydrofuran was added methylmagnesium bromide (11.6 mL, 34.8 mmol) drop-wise. After stirring at ambient temperature for 25 min, 1N hydrochloric acid was added and the mixture extracted with two portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to provide the title compound which was used without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.84 (d, J=1.9 Hz, 2H); 7.58 (d, J=1.8 Hz, 1H); 2.63 (s, 3H). the mixture extracted with two portions of ethyl acetate The combined organic layers were dried over magnesium sulfate concentrated in vacuo

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

Procedure: To a solution of 3,5-dichlorobenzoyl chloride (5 g, 23.9 mmol) in 50 mL of dichloromethane at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (2.56 g, 26.3 mmol) and pyridine (4.3 mL, 52.6 mmol). The cold bath was removed and the mixture stirred at ambient temperature for 16 hours, diluted with water and extracted with two portions of dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (SiO2, 20% ethyl acetate/hexanes) to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ: 7.61 (d, J=1.9 Hz, 2H); 7.50 (d, J=1.9 Hz, 1H); 3.60 (s, 3H); 3.40 (s, 3H). The cold bath was removed diluted with water extracted with two portions of dichloromethane The combined organic layers were dried over magnesium sulfate concentrated in vacuo the residue purified by flash column chromatography (SiO2, 20% ethyl acetate/hexanes)

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

Procedure: To a solution of the intermediate from step A (2.1 g, 11.6 mmol) in anhydrous THF (80 mL) cooled to −78° C. under a N2 atmosphere was added LHMDS (1.0 M solution in THF, 11.6 mL). After 5 minutes a solution of 3,5-dichloro-N-methoxy-N-methyl benzamide (2.71 g, 11.6 mmol) in THF (20 mL) was added to the reaction. The reaction was slowly warmed to 0° C. over 30 minutes and then quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:10 ethyl acetate-hexanes to give the title compound as a bright yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.07 (d, J=1.8 Hz, 2H), 7.66 (t, J=1.9 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.6 (d, J=8.7 Hz, 2H). quenched with saturated NH4Cl solution The resulting bi-phasic mixture was extracted with EtOAc (3×) The organic layer was washed with brine dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by flash chromatography

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-methoxy-1-ethynyl benzene (0.57 g, 4.27 mmol) in 20 mL of anhydrous THF cooled to −78° C. under a N2 atmosphere was added nButLi (3.2 mL, 5.12 mmol). After 5 minutes a solution of 3,5-dichloro-N-methoxy-N-methylbenzamide (1.0 g, 4.27 mmol) in THF (10 mL) was added to the reaction. The reaction was slowly warmed to 40° C. over 30 minutes and then quenched with saturated NH4Cl solution. The resulting bi-phasic mixture was extracted with EtOAc (3×). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 1:10 ethyl acetate-hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): δ 8.09 (d, J=2.0 Hz, 2H), 7.7 (d, J=7.1 Hz, 2H), 7.64 (t, J=1.8 Hz, 1H), 7.0 (d, J=8.7 Hz, 1H), 3.91 (s, 3H). quenched with saturated NH4Cl solution The resulting bi-phasic mixture was extracted with EtOAc (3×) The organic layer was washed with brine dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by flash chromatography

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