5-Chloro-2-methylaniline → 6-chloro-1H-indazole

HRID 2203331Notes

Reaction equation

HRID 2203331 reaction equation
C(OC(=O)C)(=O)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)[NH2:14].C([O-])(=O)C.[K+].[N:22](OC(C)(C)C)=O.O.[OH-].[Li+]>O.C1COCC1.CO.C1C=CC=CC=1>[Cl:8][C:9]1[CH:15]=[C:13]2[C:12]([CH:16]=[N:22][NH:14]2)=[CH:11][CH:10]=1

Participants

10

Reactant 5

HCID 72605-Chloro-2-methylanilineHCID 7918Acetic AnhydrideHCID 10906Tert-Butyl nitriteHCID 168937Lithium hydroxide, monohydrateHCID 517044Potassium Acetate

Product 1

HCID 4175246-chloro-1H-indazole

Reagents, catalysts & solvents 4

HCID 241BenzeneSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

Acetic anhydride (10.0 mL, 106 mmol) was added dropwise to a benzene solution (110 mL) containing 5-chloro-2-methylaniline (5.0 g, 35.3 mmol) and potassium acetate (3.8 g, 38.7 mmol) at room temperature. After 10 minutes the reaction mixture, which had formed a thick white suspension, was heated to 80° C. Tert-butyl nitrite (6.99 mL, 90%, 53.0 mmol) was added over 20 minutes. The reaction mixture was kept at 80° C. overnight. The reaction was then cooled to room temperature and concentrated. The residue was dissolved in MeOH and stirred for 10 minutes. The solution was concentrated and to the residue was added MeOH (175 mL), THF (30 mL), water (60 mL) and lithium hydroxide monohydrate (8 g, 195 mmol). The solution was then stirred overnight at room temperature. The solution was then concentrated and the residue partitioned between EtOAc and 0.5 M NaOH aq. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the indicated product. The material was used in Step B without further purification. 1H NMR (400 MHz, CH3CN-d3): δ 11.20 (broad s, 1H); 8.01 (s, 1H); 7.75-7.70 (m, 1H); 7.60 (s, 1H); 7.13 (dd, J=8.6, 1.7 Hz, 1H). m/z=153.0 (M+H).

Workup

  1. customwhich had formed a thick white suspension
  2. waitThe reaction mixture was kept at 80° C. overnight
  3. temperatureThe reaction was then cooled to room temperature
  4. concentrationconcentrated
  5. dissolutionThe residue was dissolved in MeOH
  6. concentrationThe solution was concentrated and to the residue
  7. stirringThe solution was then stirred overnight at room temperature
  8. concentrationThe solution was then concentrated
  9. customthe residue partitioned between EtOAc and 0.5 M NaOH aq. The aqueous phase
  10. extractionwas extracted twice with EtOAc
  11. washThe combined organics were washed with brine
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customto give the indicated product
  16. customThe material was used in Step B without further purification

Sources & evidence

ORD record
ord-5bee398089e44168ae8e6cd9cfa9939e
Source dataset
uspto-grants-2016_06
Patent number
US09365574B2

Reaction notes

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