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]
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.
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