Acetic Anhydride → 1-Acetyl-5-(acetoxymethyl)indazole

HRID 1634155Notes

Reaction equation

HRID 1634155 reaction equation
[OH:1][CH2:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[C:11]([O-:14])(=O)[CH3:12].[K+].[C:16]([O:19]C(=O)C)(=O)[CH3:17].C(O[N:29]=O)CC(C)C.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:16]([N:7]1[C:6]2[C:5](=[CH:4][C:3]([CH2:2][O:1][C:11](=[O:14])[CH3:12])=[CH:9][CH:8]=2)[CH:10]=[N:29]1)(=[O:19])[CH3:17]

Participants

8

Reactant 5

HCID 7918Acetic Anhydride2×HCID 8053Isoamyl NitriteHCID 2855718-Crown-6HCID 517044Potassium AcetateHCID 1514189(4-Amino-3-methylphenyl)methanol2×

Product 1

HCID 107995691-Acetyl-5-(acetoxymethyl)indazoleYield 92.2%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
45 °C

Procedure

To a suspension of 2-methyl-4-(hydroxymethyl)aniline (compound 12-2, 4.0 g, 29 mmol) and potassium acetate (Aldrich, 8.6 g, 88 mmol) in chloroform (Calbiochem, 60 mL), was added acetic anhydride (Aldrich, 8.3 mL, 88 mmol) at room temperature, and the temperature was allowed to increase to 45° C. The mixture was then heated to reflux temperature for 2 hours under nitrogen. After cooling to room temperature, isoamylnitrite (Aldrich, 7.8 mL, 88 mmol) and 18-crown-6 (Aldrich, 1.5 g, 0.6 mmol) were added. The reaction mixture was heated at its reflux temperature for 28 hours. After returning to room temperature, the mixture was further treated with acetic anhydride (10 mL) and the solution was stirred at room temperature for 12 hours. The reaction mixture was diluted with methylene chloride (600 mL) and washed with saturated aqueous NaHCO3 aqueous solution (300 mL), water (300 mL) and brine (50 mL). After drying (Na2SO4), the organic solvent was removed under vacuum to give a yellow oil which was purified by flash chromatography on silica gel (85:15 hexane-ethyl acetate) to yield the title compound (12-3, 6.21 g, 91%). TLC Rf 0.45 (70:30 of hexane-ethyl acetate); MS (electrospray) 233 (M+1); 1H N MR (CDCl3) δ 2.12 (s, 3H), 2.79 (app d, 3H, J=0.4 Hz), 5.23 (s, 2H), 7.56 (dd, 1H, J=8.8, 1.6 Hz), 7.74 (t, 1H, J=0.8 Hz), 8.12 (s, 1H), 8.43 (dd, 1H, J 8.8, 0.6 Hz).

Workup

  1. temperatureThe mixture was then heated
  2. temperatureto reflux temperature for 2 hours under nitrogen
  3. temperatureAfter cooling to room temperature
  4. temperatureThe reaction mixture was heated at its
  5. temperaturereflux temperature for 28 hours
  6. customAfter returning to room temperature
  7. washwashed with saturated aqueous NaHCO3 aqueous solution (300 mL), water (300 mL) and brine (50 mL)
  8. dry with materialAfter drying (Na2SO4)
  9. customthe organic solvent was removed under vacuum
  10. customto give a yellow oil which
  11. customwas purified by flash chromatography on silica gel (85:15 hexane-ethyl acetate)

Sources & evidence

ORD record
ord-f8b484e6afaa4cf2bc5094b40a49f5d6
Source dataset
uspto-grants-2003_01
Patent number
US06506760B1

Reaction notes

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