Methyl 2-Bromo-4-chlorobenzoate → (2-Bromo-4-chlorophenyl)methanol

Temperature

-78 °C

A 1.0 M solution of diisobutylaluminum hydride in toluene (43 mL, 0.043 mol) was added slowly drop-wise to a −78° C. solution of 2-bromo-4-chloro-benzoic acid methyl ester (10.57 g, 0.042 mol) in toluene (50 mL) and hexanes (425 mL). The reaction mixture was stirred at −78° C. for 1.5 hours. After this time, a white solid had precipitated out of solution. The reaction mixture was quenched at −78° C. with ethyl acetate (100 mL). Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature. The organic phase was separated, dried over Na2SO4, filtered, and concentrated to a clear oil. TLC (30% ethyl acetate/hexanes) and 1H NMR revealed a mixture with unreacted 2-bromo-4-chloro-benzoic acid methyl ester as the major component. The crude material was dissolved in toluene (300 mL), and the resulting solution was cooled to −78° C. A 1.0 M solution of diisobutylaluminum hydride in toluene (55 mL, 0.055 mol) was added slowly drop-wise to the reaction mixture. The reaction mixture was warmed to −45° C. and stirred at this temperature for 35 minutes. At this time, TLC (10% ethyl acetate/hexanes) indicated nearly complete consumption of the starting material. The reaction mixture was quenched at −45° C. with ethyl acetate. Saturated aqueous sodium potassium tartrate was added, and the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. The organic phase was separated, dried over Na2SO4, and concentrated to a yellow oil. A solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel, and the dry silica gel-supported product was loaded onto a 120 g silica gel column. Flash chromatography was carried out using an ISCO purification system (95:5 hexanes-ethyl acetate ramped to 4:1 hexanes-ethyl acetate). (2-Bromo-4-chloro-phenyl)-methanol was isolated as 5.57 g (60% yield) of a white solid.

1. customAfter this time, a white solid had precipitated out of solution
2. customThe reaction mixture was quenched at −78° C. with ethyl acetate (100 mL)
3. additionSaturated aqueous sodium potassium tartrate was added
4. temperaturethe reaction mixture was warmed to room temperature
5. customThe organic phase was separated
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated to a clear oil
9. dissolutionThe crude material was dissolved in toluene (300 mL)
10. temperaturethe resulting solution was cooled to −78° C
11. temperatureThe reaction mixture was warmed to −45° C.
12. stirringstirred at this temperature for 35 minutes
13. customconsumption of the starting material
14. customThe reaction mixture was quenched at −45° C. with ethyl acetate
15. additionSaturated aqueous sodium potassium tartrate was added
16. temperaturethe reaction mixture was warmed to room temperature
17. stirringstirred at room temperature for 1 hour
18. customThe organic phase was separated
19. dry with materialdried over Na2SO4
20. concentrationconcentrated to a yellow oil
21. customA solution of this crude product and dichloromethane (200 mL) was evaporated onto silica gel
22. customan ISCO purification system (95:5 hexanes-ethyl acetate ramped to 4:1 hexanes-ethyl acetate)

ORD record

ord-7380747b469447f189a9dc3f7de00d23

Source dataset

uspto-grants-2012_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08124629B2