Sulfuric Acid → 5-Hydroxy-2-methylbenzonitrile

HRID 1968978Notes

Reaction equation

HRID 1968978 reaction equation
S(=O)(=O)(O)O.N[C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[C:12]#[N:13].N([O-])=[O:17].[Na+].NC(N)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[OH:17][C:7]1[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[C:12]#[N:13]

Participants

7

Reactant 5

HCID 1118Sulfuric Acid2×HCID 1176UreaHCID 24436Sodium SulfateHCID 27353655-Amino-2-methylbenzonitrileHCID 23668193Sodium Nitrite

Product 1

HCID 594440865-Hydroxy-2-methylbenzonitrileYield 57.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent4×

Conditions

Temperature
15 °C

Procedure

Concentrated sulfuric acid (5 mL, 94 mmol) was added to H2O (10 mL) (causing an exotherm). While the diluted acid was still hot, 5-amino-2-methylbenzonitrile (826 mg, 6.25 mmol) was added giving a clear solution. This was cooled to 15° C. (during which time a precipitate occurred) and 8 g of ice was added. As soon as the temperature was below 5° C., a solution of sodium nitrite (522 mg, 7.57 mmol) in H2O (5 mL) was added from a syringe (with the needle extended below the surface of the liquid) keeping the internal temperature below 5° C. The solution went clear after 5 min of stirring and then cold H2O (5 mL), urea (59 mg, 0.97 mmol) and ice (5 g) were added sequentially. In a separate flask H2O (5 mL) was added to sodium sulfate (4.75 g, 33.4 mmol) under an atmosphere of argon. Concentrated sulfuric acid (10 mL) was cautiously added and the reaction heated to reflux. The diazonium species was added to the refluxing mixture in portions and the heating continued for 2 h (NOTE: Blast shield used during heating). The mixture was cooled to rt and extracted with Et2O (2×). The combined organics were washed with H2O and 10% Na2CO3 solution before being extracted with 10% NaOH solution. The NaOH solution was acidified with concentrated HCl and then extracted with Et2O (2×). The combined organics from this second extraction were dried (Na2SO4) and concentrated by rotary evaporation to give a light brown solid which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 5-hydroxy-2-methylbenzonitrile (D90, 476 mg, 52%) as an orange solid.

Workup

  1. customgiving a clear solution
  2. additionwas added
  3. customwas below 5° C.
  4. customthe internal temperature below 5° C
  5. temperaturethe reaction heated to reflux
  6. waitthe heating continued for 2 h
  7. temperature(NOTE: Blast shield used during heating)
  8. temperatureThe mixture was cooled to rt
  9. extractionextracted with Et2O (2×)
  10. washThe combined organics were washed with H2O and 10% Na2CO3 solution
  11. extractionbefore being extracted with 10% NaOH solution
  12. extractionextracted with Et2O (2×)
  13. extractionThe combined organics from this second extraction
  14. dry with materialwere dried (Na2SO4)
  15. concentrationconcentrated by rotary evaporation
  16. customto give a light brown solid which
  17. customwas purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM)

Sources & evidence

ORD record
ord-4b11288ab3fe4123a9f7bb191ae438df
Source dataset
uspto-grants-2013_04
Patent number
US08426443B2

Reaction notes

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