Tetrahydrofuran → (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one

Temperature

-15 °C

A 250 mL three-necked flask equipped with air driven stirrer and 250 mL addition funnel was charged with anhydrous THF (50 mL) and (R)-MeCBS (1.6 mL, 1 M, 1.6 mmol). The solution was cooled to −15° C. and BH3-THF (32.4 mL, 1 M, 32.4 mmol) added in a steady stream. Charge the 250 mL addition funnel with 3-(1,3-Benzodioxol-5-yl)-6-propoxy-1H-inden-1-one (10 g, 32.4 mmol) and anhydrous THF (50 mL) and add the solution dropwise over 1.5 h period while maintaining the internal reaction temperature between −10 to −15° C. Upon complete addition, stir the reaction mixture for 0.5 h at −15° C., cool the solution to −25° C. and add CH3OH (20 mL) dropwise over 20 minutes while maintaining the internal reaction temperature below −15° C. Warm the solution to 20° C. over 0.5 h and stir the solution for an additional 0.5 h at ambient temperature. Cool the solution to 0° C. and add Et3N (1 mL, 81 mmol) to the reaction mixture dropwise over 15 minutes while maintaining the internal reaction temperature below 5° C. Add 1,1-bis(triphenylphosphine) nickel(II) chloride (211 mg, 3.24 mmol) and warm the reaction mixture to 60° C. for 4 h. Concentrate the solution to 1/4 volume, cool to room temperature, add Celite (12 g) and then hexanes (85 ml). Stir the mixture vigorously for 10 min and filter through a SiO2 (10 g) and Celite (10 g) pad. Wash the filter pad with THF/hexane (45 mL/120 mL), combine the filtrates, and transfer to a 500 mL round-bottomed flask. Concentrate the solution in vacuo until a precipitate forms, add hexane (40 mL) and cool the solution to −15 CC for 8 h. Filter the precipitate, wash the filter cake with cold (0° C.) hexane solution and dry under vacuum to afford (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one as a light yellow solid (8.1 g, 81%, 88% e.e.): mp 68.0-69.5° C.

1. customA 250 mL three-necked flask equipped with air
2. additionstirrer and 250 mL addition funnel
3. additionCharge
4. additionadd the solution dropwise over 1.5 h period
5. temperaturewhile maintaining the internal reaction temperature between −10 to −15° C
6. additionUpon complete addition
7. temperaturecool the solution to −25° C.
8. temperaturewhile maintaining the internal reaction temperature below −15° C
9. temperatureWarm the solution to 20° C. over 0.5 h
10. stirringstir the solution for an additional 0.5 h at ambient temperature
11. temperatureCool the solution to 0° C.
12. temperaturewhile maintaining the internal reaction temperature below 5° C
13. concentrationConcentrate the solution to 1/4 volume
14. temperaturecool to room temperature
15. additionadd Celite (12 g)
16. stirringStir the mixture vigorously for 10 min
17. filtrationfilter through a SiO2 (10 g) and Celite (10 g) pad
18. washWash the filter pad with THF/hexane (45 mL/120 mL)
19. concentrationConcentrate the solution in vacuo until a precipitate forms
20. additionadd hexane (40 mL)
21. temperaturecool the solution to −15 CC for 8 h
22. filtrationFilter the precipitate
23. washwash the filter cake with cold (0° C.) hexane solution
24. customdry under vacuum

ORD record

ord-1c471548d8e847c5a5b650da7c97ba64

Source dataset

uspto-grants-2002_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06355813B1