N-(hydroxymethyl)-2,2-dimethylpropanamide

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:; See reaction.notes.procedure_details.

Procedure: Cool sulfuric acid (3.67 mL) to 0° C., and add 2-methylbenzoic acid (500 mg, 3.67 mmol, 1.0 equiv) and N-(hydroxymethyl)-2,2-dimethylpropanamide (506 mg, 3.86 mmol, 1.05 equiv). Allow the mixture to warm to room temperature, and stir overnight. Dilute with water (25 mL) and extract with EtOAc (50 mL). Dry the organic layer over MgSO4, filter, and concentrate under reduced pressure to give the crude compound. Purify the material by reverse-phase HPLC on an XBridge Prep C18 5 μM OBD 30×75 mm column, eluting with a gradient of 5-50% (0.1% TFA in acetonitrile) in (0.1% TFA in water) to give the title compound (255 mg, 28%). 1H NMR (DMSO-d6, 400 MHz): δ 12.76 (s, 1H), 8.09 (t, 1H, J=6.0 Hz), 7.67 (d, 1H, J=1.6 Hz), 7.25 (dd, 1H, J=8.0, 1.6 Hz), 7.21 (d, 1H, J=8.0 Hz), 4.22 (d, 2H, J=6.0 Hz), 2.46 (s, 3H), 1.10 (s, 9H). extract with EtOAc (50 mL) Dry the organic layer over MgSO4 filter concentrate under reduced pressure to give the crude compound Purify the material by reverse-phase HPLC on an XBridge Prep 5 μM OBD 30×75 mm column, eluting with a gradient of 5-50% (0.1% TFA in acetonitrile) in (0.1% TFA in water)

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

Procedure: To a mixture of 2,2-dimethylpropanamide (5.0 g, 49.4 mmol, 1.0 equiv) and aqueous sodium hydroxide (1 M, 0.494 mL, 0.494 mmol, 0.01 equiv), add aqueous formaldehyde (13.31 M, 3.71 mL, 49.4 mmol, 1.0 equiv). Stir at room temperature for 2 h, and concentrate under reduced pressure to give a white solid. Dilute the crude material with dichloromethane, dry over MgSO4, filter, and concentrate under reduced pressure to give the title compound as a white solid (6.4 g, 99%). 1H NMR (DMSO-d6, 400 MHz): δ 8.14 (br s, 1H), 5.40 (t, 1H, J=6.7 Hz), 4.46 (app t, 2H, J=6.6 Hz), 1.06 (s, 9H). concentrate under reduced pressure to give a white solid dry over MgSO4 filter concentrate under reduced pressure

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

Procedure: To a mixture of 2,2-dimethylpropanamide (5.0 g, 49.4 mmol, 1.0 equiv) and aqueous sodium hydroxide (1 M, 0.494 mL, 0.494 mmol, 0.01 equiv), add aqueous formaldehyde (13.31 M, 3.71 mL, 49.4 mmol, 1.0 equiv). Stir at room temperature for 2 h, and concentrate under reduced pressure to give a white solid. Dilute the crude material with dichloromethane, dry over MgSO4, filter, and concentrate under reduced pressure to give the title compound as a white solid (6.4 g, 99%). 1H NMR (DMSO-d6, 400 MHz): δ 8.14 (br s, 1H), 5.40 (t, 1H, J=6.7 Hz), 4.46 (app t, 2H, J=6.6 Hz), 1.06 (s, 9H). concentrate under reduced pressure to give a white solid dry over MgSO4 filter concentrate under reduced pressure

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

Procedure: A flask is charged with N-hydroxymethyl-2,2-dimethyl-propionamide (0.500 g, 3.81 mmol) and dichloromethane (4 mL). Oxalyl chloride (0.8 mL, 9.52 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. Concentration in vacuo gives N-chloromethyl-2,2-dimethyl-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H), 5.31 (s, 2H). Concentration in vacuo

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

Procedure: A flask is charged with N-hydroxymethyl-2,2-dimethyl-propionamide (0.500 g, 3.81 mmol) and dichloromethane (4 mL). Oxalyl chloride (0.8 mL, 9.52 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. Concentration in vacuo gives N-chloromethyl-2,2-dimethyl-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H), 5.31 (s, 2H). Concentration in vacuo

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask is charged with 2,2-dimethyl-propionamide (1.00 g, 9.98 mmol), p-formaldehyde (0.736 g, 9.98 mmol), and potassium carbonate (0.054 g, 3.95 mmol). The reaction mixture is stirred at 75° C. for 16 h, whereupon it is cooled to room temperature and diluted with acetone. Filtration and concentration of the filtrate give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 4:1) to afford N-hydroxymethyl-2,2-dimethyl-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.25 (s, 9H), 4.73 (d, J=7.1 Hz, 2H). is cooled to room temperature Filtration and concentration of the filtrate give a residue which is purified by silica gel flash chromatography (heptane-ethyl acetate, 4:1)

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

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