Benzyl Bromide → (1S,4R)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene

Temperature

0 °C

To a round bottom flask containing commercially available, (1S,4R)-2-azabicyclo[2.2.1]hept-5-en-3-one (2.0 g, 18.3 mmol), in THF (100 mL) at 0° C. was added a solution of LiAlH4 (1 M in THF, 40.3 mL, 40.3 mmol), and the reaction mixture was refluxed overnight. The reaction mixture was then cooled to 0° C. and carefully quenched by the dropwise addition of H2O (15 mL). Celite and solid Na2CO3 were added to the slurry and the reaction mixture was vigorously stirred at room temperature for 3 h. The slurry was then filtered and the solids washed with THF. Benzyl bromide (2.4 mL, 20.2 mmol) and an aqueous solution of Na2CO3 (3.2 g in 30 mL H2O) were added to the filtrate and the reaction mixture stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was extracted with EtOAc (3×). The combined organics were washed with H2O, brine, dried with MgSO4, filtered, and concentrated to provide crude (1S,4R)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene as a yellow oil, which was directly hydroborated according to the procedure of F. Carroll et al. [J. Med. Chem. 1992, 35, 2184-2191]. The crude alcohol was purified by silica gel chromatography (0-15% MeOH (with 5% NH4OH) in DCM) to give intermediate B-6 as a clear oil (2.66 g, 13.1 mmol, 71% over 3 steps). MS (ESI) mass calcd for C13H17NO, 203.1. m/z found 204.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ 7.39-7.28 (m, 4H), 7.26-7.21 (m, 1H), 4.18-4.09 (m, 1H), 3.76-3.66 (m, 2H), 3.06 (br. s, 1H), 2.51 (dt, J=9.0, 3.0 Hz, 1H), 2.44-2.35 (m, 2H), 1.90-1.81 (m, 1H), 1.68-1.53 (m, 2H), 1.38-1.30 (m, 1H).

1. additionTo a round bottom flask containing commercially available
2. temperaturethe reaction mixture was refluxed overnight
3. customcarefully quenched by the dropwise addition of H2O (15 mL)
4. additionCelite and solid Na2CO3 were added to the slurry
5. filtrationThe slurry was then filtered
6. washthe solids washed with THF
7. stirringthe reaction mixture stirred at room temperature overnight
8. customUpon completion of the reaction
9. extractionthe reaction mixture was extracted with EtOAc (3×)
10. washThe combined organics were washed with H2O, brine
11. dry with materialdried with MgSO4
12. filtrationfiltered
13. concentrationconcentrated

ORD record

ord-a2329fb1ffe249d786fdede207879f23

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969352B2