tert-butyl N-(propan-2-ylamino)carbamate

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

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70 mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture was stirred for 7 h at RT before the addition of DMF (40 mL) and stirring overnight. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-90% ethyl acetate in cyclohexane) to give N′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester as a white solid (3.02 g, quantitative yield). LCMS RT=4.76 min, [M+H]+=465/467. 1H NMR 400 MHz (DMSO-d6) δ: 8.62 (1H, s), 8.40 (1H, d, J=8.59 Hz), 7.69 (1H, s), 7.23-7.22 (2H, m), 4.81 (1H, s), 4.44 (4H, s), 1.32 (9H, s), 1.13 (6H, d, J=6.64 Hz) The reaction mixture was concentrated in vacuo the resultant residue partitioned between DCM and water The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution brine, dried (Na2SO4) concentrated in vacuo

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70 mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture was stirred for 7 h at RT before the addition of DMF (40 mL) and stirring overnight. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-90% ethyl acetate in cyclohexane) to give N′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester as a white solid (3.02 g, quantitative yield). LCMS RT=4.76 min, [M+H]+=465/467. 1H NMR 400 MHz (DMSO-d6) δ: 8.62 (1H, s), 8.40 (1H, d, J=8.59 Hz), 7.69 (1H, s), 7.23-7.22 (2H, m), 4.81 (1H, s), 4.44 (4H, s), 1.32 (9H, s), 1.13 (6H, d, J=6.64 Hz) The reaction mixture was concentrated in vacuo the resultant residue partitioned between DCM and water The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution brine, dried (Na2SO4) concentrated in vacuo

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93 mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reaction mixture was stirred at RT for 72 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid, then saturated sodium bicarbonate solution followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The oil was extracted with diethyl ether (×5) and the diethyl ether extracts concentrated in vacuo before being triturated with pentane to give the title compound as a light brown solid (6.14 g, 12.7 mmol, 80%). LCMS: RT=5.02 min, [M+H]+=482/484. before being concentrated in vacuo The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid The organic layer was dried (Na2SO4) filtered concentrated in vacuo to give a brown oil The oil was extracted with diethyl ether (×5) the diethyl ether extracts concentrated in vacuo before being triturated with pentane

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

Procedure: Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaBH3CN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCO3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5% MeOH in DCM as eluent to collect tert-butyl 2-isopropylhydrazinecarboxylate 3 (0.4 g, 77% yield): mp=47-49° C.; Rf=0.44 (5% MeOH in DCM); 1H NMR 300 MHz (CDCl3) d 6.03 (s, N—H, 1H), 3.92 (s, N—H, 1H), 3.14 (m, 1H), 1.46 (s, 9H), 1.02 (d, 6H, J=6 Hz); 13C NMR 300 MHz (CDCl3) d 157.2, 80.8, 51.2, 28.7, 21.0. was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0 the solvent was removed by rotary evaporation the residue was partitioned between EtOAc (30 mL) and brine The organic phase was extracted with sat. NaHCO3, 20 mL and brine evaporated to a residue dissolved in 10 mL of ethanol left to stir at rt for 30 min The solvent was removed by rotary evaporation extracted with water The organic layer was evaporated under reduced pressure the residue was purified by column chromatography

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

Procedure: tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).

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

Procedure: tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).

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

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93 mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reaction mixture was stirred at RT for 72 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid, then saturated sodium bicarbonate solution followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The oil was extracted with diethyl ether (×5) and the diethyl ether extracts concentrated in vacuo before being triturated with pentane to give the title compound as a light brown solid (6.14 g, 12.7 mmol, 80%). LCMS: RT=5.02 min, [M+H]+=482/484. before being concentrated in vacuo The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid The organic layer was dried (Na2SO4) filtered concentrated in vacuo to give a brown oil The oil was extracted with diethyl ether (×5) the diethyl ether extracts concentrated in vacuo before being triturated with pentane

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93 mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reaction mixture was stirred at RT for 72 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid, then saturated sodium bicarbonate solution followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The oil was extracted with diethyl ether (×5) and the diethyl ether extracts concentrated in vacuo before being triturated with pentane to give the title compound as a light brown solid (6.14 g, 12.7 mmol, 80%). LCMS: RT=5.02 min, [M+H]+=482/484. before being concentrated in vacuo The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid The organic layer was dried (Na2SO4) filtered concentrated in vacuo to give a brown oil The oil was extracted with diethyl ether (×5) the diethyl ether extracts concentrated in vacuo before being triturated with pentane

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (1.92 g, 6.2 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (1.30 g, 7.5 mmol) in DMF (20 mL) at 0° C. was added DIPEA (2.70 mL, 15.5 mmol) and HATU (3.54 g, 9.3 mmol). The reaction mixture was stirred for 7 h at RT before the addition of DMF (40 mL) and stirring overnight. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-90% ethyl acetate in cyclohexane) to give N′-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester as a white solid (3.02 g, quantitative yield). LCMS RT=4.76 min, [M+H]+=465/467. 1H NMR 400 MHz (DMSO-d6) δ: 8.62 (1H, s), 8.40 (1H, d, J=8.59 Hz), 7.69 (1H, s), 7.23-7.22 (2H, m), 4.81 (1H, s), 4.44 (4H, s), 1.32 (9H, s), 1.13 (6H, d, J=6.64 Hz) The reaction mixture was concentrated in vacuo the resultant residue partitioned between DCM and water The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed sequentially with 10% citric acid solution, saturated sodium bicarbonate solution brine, dried (Na2SO4) concentrated in vacuo

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

Procedure: To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93 mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reaction mixture was stirred at RT for 72 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid, then saturated sodium bicarbonate solution followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The oil was extracted with diethyl ether (×5) and the diethyl ether extracts concentrated in vacuo before being triturated with pentane to give the title compound as a light brown solid (6.14 g, 12.7 mmol, 80%). LCMS: RT=5.02 min, [M+H]+=482/484. before being concentrated in vacuo The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid The organic layer was dried (Na2SO4) filtered concentrated in vacuo to give a brown oil The oil was extracted with diethyl ether (×5) the diethyl ether extracts concentrated in vacuo before being triturated with pentane