1-Bromo-3-chlorobenzene → (R)-Tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate

Temperature

-78 °C

To a solution of 1-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrous THF (150 mL) cooled to −78° C. was added dropwise a solution of 2.5 M n-BuLi in hexane (31.3 mL, 78.34 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.8 g, 65.3 mmol) in anhydrous THF (50 mL) was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl (250 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc 5:95) to give (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (12.9 g, 51%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, 1H), 2.00 (m, 1H), 2.71-2.78 (m, 1H), 2.93 (m, 2H), 3.30-3.35 (m, 1H), 4.22 (m, 1H), 7.39-7.42 (t, 1H), 7.52 (d, 1H), 7.89 (d, 1H), 7.90 (m, 1H). MS (E/Z): 324 (M+H+).

1. additionAfter addition
2. temperatureto warm to rt
3. stirringstirred for 2 h
4. customThe mixture was quenched with saturated NH4Cl (250 mL)
5. extractionextracted with EtOAc (3×150 mL)
6. washThe combined organic layers were washed with brine
7. dry with materialdried over Na2SO4
8. concentrationconcentrated in vacuo
9. customThe residue was purified by flash column chromatography (PE/EtOAc 5:95)

ORD record

ord-dbeae7604d5f46fa8b5cdd3475946cee

Source dataset

uspto-grants-2013_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08455521B2