tert-butyl N-(cyclobutylamino)carbamate

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

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.88 g, 4.72 mmol) was dissolved in ethanol (45 mL). Allyl bromide (0.82 mL, 9.44 mmol), potassium carbonate (0.65 g, 4.72 mmol), and lithium iodide (0.063 g, 0.47 mmol) were added sequentially. The reaction was stirred at reflux for 18 h. The mixture was cooled to 25° C., concentrated in vacuo, taken up in water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-20% ethyl acetate in hexanes) afforded the desired product, N′-allyl-N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.98 g, 4.34 mmol, 92%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.36 (9H, s), 1.50-1.62 (2H, m), 1.82-1.88 (4H, m), 3.13 (2H, d, J=6.0 Hz), 3.34-3.39 (1H, m), 5.03 (1H, d, J=10.0 Hz), 5.14 (1H, d, J=16.8 Hz), 5.71-5.81 (1H, m), 7.59 (1H, bs). LC-MS (ESI) calcd for C7H14N2 (free hydrazine) 126.20, found 127.0 [M+H+]. at reflux for 18 h concentrated in vacuo extracted with ethyl acetate (3×20 mL) dried over magnesium sulfate filtered concentrated in vacuo to afford a yellow oil Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-20% ethyl acetate in hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclobutanone (8.19 g, 116.85 mmol) was dissolved in ethanol (60 mL). tert-Butyl carbazate (15.64 g, 118.34 mmol) was added. The reaction was stirred at 25° C. for 2.5 h before it was concentrated in vacuo. The residue was re-dissolved in ethanol (60 mL). Acetic acid (14.09 mL, 246.14 mmol) and sodium cyanoborohydride (15.46 g, 246.02 mmol) were added. The reaction was stirred at 25° C. for 48 h. The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached). The resulting mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes) afforded the desired product, N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (5.42 g, 29.10 mmol, 25%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.62-1.70 (1H, m), 1.73-1.82 (1H, m), 1.84-1.94 (2H, m), 2.07-2.15 (2H, m), 3.56-3.63 (1H, m). was concentrated in vacuo The residue was re-dissolved in ethanol (60 mL) The reaction was stirred at 25° C. for 48 h The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached) The resulting mixture was extracted with ethyl acetate (3×150 mL) dried over magnesium sulfate filtered concentrated in vacuo to afford a yellow oil Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclobutanone (8.19 g, 116.85 mmol) was dissolved in ethanol (60 mL). tert-Butyl carbazate (15.64 g, 118.34 mmol) was added. The reaction was stirred at 25° C. for 2.5 h before it was concentrated in vacuo. The residue was re-dissolved in ethanol (60 mL). Acetic acid (14.09 mL, 246.14 mmol) and sodium cyanoborohydride (15.46 g, 246.02 mmol) were added. The reaction was stirred at 25° C. for 48 h. The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached). The resulting mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes) afforded the desired product, N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (5.42 g, 29.10 mmol, 25%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.62-1.70 (1H, m), 1.73-1.82 (1H, m), 1.84-1.94 (2H, m), 2.07-2.15 (2H, m), 3.56-3.63 (1H, m). was concentrated in vacuo The residue was re-dissolved in ethanol (60 mL) The reaction was stirred at 25° C. for 48 h The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached) The resulting mixture was extracted with ethyl acetate (3×150 mL) dried over magnesium sulfate filtered concentrated in vacuo to afford a yellow oil Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes)

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

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

Procedure: A solution of tert-butyl 2-cyclobutylidenehydrazinecarboxylate (5.0 g, 27.1 mmol) in THF (50 mL) was added dropwise over 1.5 hours to a solution of borane tetrahydrofuran complex (33.9 mL, 33.9 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours. Borane tetrahydrofuran (3 mL, 3 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The resulting mixture was quenched cautiously by the addition of water (50 mL) and the mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (2×200 mL), using brine to aid the separation. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound. the mixture was stirred at room temperature overnight The resulting mixture was quenched cautiously by the addition of water (50 mL) the mixture was concentrated under reduced pressure The residue was diluted with water (30 mL) extracted with EtOAc (2×200 mL) the separation The combined organic extracts were washed with brine dried over MgSO4 filtered the solvent was removed under reduced pressure The crude material was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.88 g, 4.72 mmol) was dissolved in ethanol (45 mL). Allyl bromide (0.82 mL, 9.44 mmol), potassium carbonate (0.65 g, 4.72 mmol), and lithium iodide (0.063 g, 0.47 mmol) were added sequentially. The reaction was stirred at reflux for 18 h. The mixture was cooled to 25° C., concentrated in vacuo, taken up in water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-20% ethyl acetate in hexanes) afforded the desired product, N′-allyl-N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (0.98 g, 4.34 mmol, 92%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.36 (9H, s), 1.50-1.62 (2H, m), 1.82-1.88 (4H, m), 3.13 (2H, d, J=6.0 Hz), 3.34-3.39 (1H, m), 5.03 (1H, d, J=10.0 Hz), 5.14 (1H, d, J=16.8 Hz), 5.71-5.81 (1H, m), 7.59 (1H, bs). LC-MS (ESI) calcd for C7H14N2 (free hydrazine) 126.20, found 127.0 [M+H+]. at reflux for 18 h concentrated in vacuo extracted with ethyl acetate (3×20 mL) dried over magnesium sulfate filtered concentrated in vacuo to afford a yellow oil Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-20% ethyl acetate in hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclobutanone (8.19 g, 116.85 mmol) was dissolved in ethanol (60 mL). tert-Butyl carbazate (15.64 g, 118.34 mmol) was added. The reaction was stirred at 25° C. for 2.5 h before it was concentrated in vacuo. The residue was re-dissolved in ethanol (60 mL). Acetic acid (14.09 mL, 246.14 mmol) and sodium cyanoborohydride (15.46 g, 246.02 mmol) were added. The reaction was stirred at 25° C. for 48 h. The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached). The resulting mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes) afforded the desired product, N′-cyclobutyl-hydrazinecarboxylic acid tert-butyl ester (5.42 g, 29.10 mmol, 25%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.62-1.70 (1H, m), 1.73-1.82 (1H, m), 1.84-1.94 (2H, m), 2.07-2.15 (2H, m), 3.56-3.63 (1H, m). was concentrated in vacuo The residue was re-dissolved in ethanol (60 mL) The reaction was stirred at 25° C. for 48 h The reaction was quenched via slow addition of saturated aqueous sodium bicarbonate solution (until pH 8 was reached) The resulting mixture was extracted with ethyl acetate (3×150 mL) dried over magnesium sulfate filtered concentrated in vacuo to afford a yellow oil Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-30% ethyl acetate in hexanes)