Acetic Anhydride → 6-(1,1-Dimethylethyl)-1H-indazole

HRID 246024Notes

Reaction equation

HRID 246024 reaction equation
[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:25](OCCC(C)C)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:11]=[C:9]2[C:8]([CH:12]=[N:25][NH:10]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 7918Acetic AnhydrideHCID 8053Isoamyl NitriteHCID 517044Potassium AcetateHCID 130899795-tert-Butyl-2-methylaniline

Product 1

HCID 533996396-(1,1-Dimethylethyl)-1H-indazoleYield 39%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a solution of 5-tert-butyl-2-methylaniline (2.48 g, 15.2 mmol) in CHCl3 (40 ml) at 0° C. was slowly added acetic anhydride (3.3 ml, 34.9 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Potassium acetate (446 mg, 4.55 mmol) was added followed by slow addition of isoamyl nitrite (4.4 ml, 32.6 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc and washed with water, sat'd NaHCO3 and brine then dried over MgSO4 and concentrated. The residue was dissolved in THF/MeOH (1:1, 40 mL) and 10% NaOH (4.5 mL) was added. The reaction mixture was stirred at room temperature for 10 min then neutralized with 1.0 M HCl, diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to afford 1.02 g (39%) of 6-tert-butyl-1H-indazole as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.03 (s, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.48 (s, 1H), 7.29 (dd, J=8.7, 1.5 Hz, 1H), 1.40 (s, 9H).

Workup

  1. customat 0° C.
  2. temperatureThe reaction mixture was heated
  3. temperatureat reflux overnight
  4. temperatureThe reaction mixture was cooled to room temperature
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in EtOAc
  7. washwashed with water
  8. dry with materialthen dried over MgSO4
  9. concentrationconcentrated
  10. dissolutionThe residue was dissolved in THF/MeOH (1:1, 40 mL)
  11. addition10% NaOH (4.5 mL) was added
  12. stirringThe reaction mixture was stirred at room temperature for 10 min
  13. additiondiluted with water
  14. extractionextracted with EtOAc (2×)
  15. washThe combined organics were washed with brine
  16. dry with materialthen dried over MgSO4
  17. concentrationconcentrated
  18. customThe residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

Sources & evidence

ORD record
ord-1d7a27e52f084e7282e3a7673eeea168
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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