Hydrochloric Acid → 1H-Indazole

Participants

Reaction Steps

6-Nitroindole (AA1, 1.0 g, 6.2 mmol) was suspended in a solution of sodium nitrite (4.3 g, 62 mmol) in H2O (123 mL). To the suspension 6N HCl was added slowly until the pH was about pH 1. The resulting mixture was stirred at about rt, with protection from light, for about 2.5 h and extracted with EtOAc (120 mL×3). The combined extracts were washed with H2O (50 mL), brine (50 mL), dried (Na2SO4) and evaporated to give 1.13 g of indazole AA2 as a yellow-pink solid. A solution of AA2 (450 mg, 2.4 mmol) and pyrrolidine (836 mg, 11.8 mmol) in ClCH2CH2Cl:DMF:HOAc (90:9:1) were stirred at about rt for about 20 min, to which was then added NaB(OAc)3H (1.25 g, 5.9 mmol) in one portion. The mixture was stirred at about rt for about 1 h, and then diluted with EtOAc (200 mL), washed with saturated NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and evaporated to afford 570 mg of AA3 as a viscous brown solid. 6-Nitroindazole AA3 (4.4 g, 17.8 mmol) was dissolved in dry THF (200 mL) under argon and 2,6-dichlorobenzyl bromide (4.3 g, 17.8 mmol) was added, followed by portionwise addition of pulverized KOH (1.17 g, 17.8 mmol) over about the next 20 min. The reaction was stirred at about rt for about 1 h and then evaporated in vacuo to an oil, which was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was separated and washed twice with water, three times with brine, dried (Na2SO4) and evaporated in vacuo to a brown solid. This was purified by flash column chromatography using DCM:MeOH (19:1) to afford 2.4 g of a tan solid which was combined with ferric chloride hexahydrate (0.30 g, 1.1 mmol) and activated charcoal (3.0 g, 0.25 mmol) in MeOH (200 mL). Dimethyl hydrazine (32 g, 0.53 mmol) was added and the reaction was refluxed for about 2 h, cooled to about rt and filtered through dicalite, which was washed several times with DCM:MeOH (4:1). The combined filtrates were evaporated in vacuo to a brown solid, which was purified by flash chromatography with DCM:MeOH:NH4OH (90:8:1) to give 1.75 g of amine AA4.

Provenance & Evidence