Acetic Anhydride → 4-bromo-1H-indazole

HRID 383251Notes

Reaction equation

HRID 383251 reaction equation
[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[N:40](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:40][NH:5]2

Participants

7

Reactant 5

HCID 7918Acetic AnhydrideHCID 8053Isoamyl NitriteHCID 2855718-Crown-6HCID 1235383-Bromo-o-toluidineHCID 517044Potassium Acetate

Product 1

HCID 223525484-bromo-1H-indazoleYield 40%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a solution of 3-bromo-2-methyl aniline (0104) (0.50 g, 2.69 mmol) in chloroform (5 mL) was added potassium acetate (0.28 g, 2.82 mmol). The mixture was cooled with ice-water bath and then acetic anhydride (0.50 mL, 5.37 mmol) was added to it. Ice-water bath was then removed and the resulting mixture was stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.14 g, 0.54 mmol) was then added followed by isoamyl nitrite (0.80 mL, 5.90 mmol). The mixture was then heated under reflux for 18 hours. The reaction mixture was allowed to cool, and was partitioned between chloroform (3×10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography (ethyl acetate in petroleum ether, 10% v/v) to give 1-(4-bromoindrazol-1-y1)-ethanone (0105) as an orange solid (0.31 g, 49%), and 4-bromo-1H-indazole (0106-3) as a pale orange solid (0.21 g, 40%). Compound 0105: LCMS: 239 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 2.80 (s, 3H), 7.41 (t, J=6.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 8.15 (s, 1H), 8.40 (d, J=6.8 Hz, 1H). Compound 0106: LCMS: 197 [M+1]+; 1H NMR (400 Hz, CDCl3) δ 7.25 (t, J=6.0 Hz, 1H), 7.34 (d, J=6.4 Hz, 1H), 7.46 (d, J=6.8 Hz, 1H), 8.12 (s, 1H).

Workup

  1. temperatureThe mixture was cooled with ice-water bath
  2. customIce-water bath was then removed
  3. customformed
  4. temperatureThe mixture was then heated
  5. temperatureunder reflux for 18 hours
  6. temperatureto cool
  7. customwas partitioned between chloroform (3×10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL)
  8. washThe combined organic extracts were washed with brine (10 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. customevaporated
  12. customto give a crude product which
  13. customwas purified by column chromatography (ethyl acetate in petroleum ether, 10% v/v)

Sources & evidence

ORD record
ord-2f160cd5bc0b456187c9c65c4442a668
Source dataset
uspto-grants-2013_02
Patent number
US08367663B2

Reaction notes

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