2,4,6-Trimethylpyridine → 3-Bromo-5-hydroxybenzonitrile

Temperature

60 °C

A solution of 3-bromo-5-methoxybenzaldehyde (4.02 g, 18.7 mmol) and hydroxylamine hydrochloride (6.50 g, 93.5 mmol) in pyridine (50 mL) and EtOH (50 mL) was heated to 65° C. for 16 h. The solvent was removed, and the remaining materials were partitioned between 1:1 EtOAc/hexanes (150 mL) and H2O (75 mL). The organic layer was washed with brine (60 mL), and the solvents were evaporated. The remaining oil was dissolved in anhydrous dioxane (50 mL), and trifluoroacetic anhydride (5.1 mL, 37.4 mmol) and pyridine (9.07 mL, 112.2 mmol) were added. The mixture was heated to 60° C. for 3 h and then cooled to RT. CHCl3 (100 mL) was added, and the organic layer was washed with H2O (2×50 mL), 5% aqueous HCl solution (30 mL), brine (30 mL), and dried with anhydrous MgSO4. The solvents were removed to provide a white solid. This solid was placed in a 150 mL flask that was flushed with nitrogen. Collidine (40 mL) and LiI (7.92 g, 59.10 mmol) were added, and the mixture was heated to 180° C. for 5 h. The reaction mixture was cooled to RT, and partitioned between H2O (400 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was acidified with 10% aqueous HCl solution, and extracted with 2:1 EtOAc/hexanes (3×125 mL). The combined organic layers were washed with H2O (100 mL), 10% aqueous HCl solution (2×50 mL), brine (75 mL), and dried with anhydrous MgSO4. The solvents were evaporated and the resulting solid was purified by flash chromatography on silica gel (10% to 40% EtOAc/hexanes) to provide 3.40 g (92%) of 3-bromo-5-hydroxybenzonitrile (116).

1. customThe solvent was removed
2. customthe remaining materials were partitioned between 1:1 EtOAc/hexanes (150 mL) and H2O (75 mL)
3. washThe organic layer was washed with brine (60 mL)
4. customthe solvents were evaporated
5. dissolutionThe remaining oil was dissolved in anhydrous dioxane (50 mL)
6. temperaturecooled to RT
7. washthe organic layer was washed with H2O (2×50 mL), 5% aqueous HCl solution (30 mL), brine (30 mL)
8. dry with materialdried with anhydrous MgSO4
9. customThe solvents were removed
10. customto provide a white solid
11. customThis solid was placed in a 150 mL flask
12. customthat was flushed with nitrogen
13. temperaturethe mixture was heated to 180° C. for 5 h
14. temperatureThe reaction mixture was cooled to RT
15. custompartitioned between H2O (400 mL) and EtOAc (100 mL)
16. customThe layers were separated
17. extractionextracted with 2:1 EtOAc/hexanes (3×125 mL)
18. washThe combined organic layers were washed with H2O (100 mL), 10% aqueous HCl solution (2×50 mL), brine (75 mL)
19. dry with materialdried with anhydrous MgSO4
20. customThe solvents were evaporated
21. customthe resulting solid was purified by flash chromatography on silica gel (10% to 40% EtOAc/hexanes)

ORD record

ord-5188cc4c5ae3465b95637c49aba084cc

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07189718B2