Reaction #1833226

Reaction equation

diisopropylamine

n-BuLi

NaH

Methyl iodide

trimethylborate

peracetic acid

5-bromo-2,2-difluorobenzo[d][1,3]dioxole

NaH

HCl

NaHSO3

→

LDA

title compound

Yield 31.2%

5-Bromo-2,2-difluoro-4-methoxybenzo[d][1,3]dioxole

Yield 31.2%

Solvents

tetrahydrofuran

water

NaCl

Conditions

Workup

1. 1
   Temperatureto warm to ambient overnight
2. 2
   TemperatureThe mixture was cooled to −30 to −40° C.
3. 3
   workup.STIRRINGThe mixture was stirred for 30 min at −30° C.
4. 4
   Temperaturewarmed to 5-10° C.
5. 5
   workup.STIRRINGstirred for 20 min
6. 6
   ExtractionThe mixture was extracted ethyl acetate (2×100 mL)
7. 7
   Washthe combined extracts were washed with saturated NaCl (50 mL)
8. 8
   Dryingdried (Na2SO4) and rotary evaporated
9. 9
   workup.DISSOLUTIONThe crude phenol was dissolved in dry DMSO (50 mL)
10. 10
    workup.STIRRINGstirred for 30 min
11. 11
    Otherto produce a clear solution
12. 12
    workup.STIRRINGthe mixture was stirred for 20 h at 20° C
13. 13
    workup.STIRRINGstirring
14. 14
    workup.WAITwas continued for 1 h
15. 15
    Extractionextracted diethyl ether (2×75 mL)
16. 16
    WashThe combined extracts were washed with water (2×20 mL), with saturated NaCl (20 mL)
17. 17
    Dryingdried (Na2SO4)
18. 18
    Otherevaporated
19. 19
    OtherThe crude material was purified by chromatography on silica with a 0-20% ethyl acetate-hexane gradient

Procedure

A solution of LDA was prepared from diisopropylamine (4.2 g, 41 mmol) and n-BuLi (2.5 M; 15.4 mL, 38 mmol) in dry tetrahydrofuran (100 mL). The solution was cooled to −70° C. and treated in portions with 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (7.0 g, 30 mmol). After 2 h at −70° C., trimethylborate (4.3 g, 41 mmol) was added in portions, stirred at −70° C. for 1.5 h and then allowed to warm to ambient overnight. The mixture was cooled to −30 to −40° C. and treated carefully with 28% peracetic acid. The mixture was stirred for 30 min at −30° C., warmed to 5-10° C., treated with 10% NaHSO3 (100 mL) solution and stirred for 20 min. The mixture was acidified by addition of 6 M HCl and diluted with saturated NaCl solution (75 mL). The mixture was extracted ethyl acetate (2×100 mL) and the combined extracts were washed with saturated NaCl (50 mL), dried (Na2SO4) and rotary evaporated. The crude phenol was dissolved in dry DMSO (50 mL), treated with 95% NaH (750 mg, 30 mmol) and stirred for 30 min to produce a clear solution. Methyl iodide (5.0 g, 35 mmol) was added in portions, and the mixture was stirred for 20 h at 20° C. An additional 200 mg NaH were added and stirring was continued for 1 h more. The mixture was poured into water (100 mL) and extracted diethyl ether (2×75 mL). The combined extracts were washed with water (2×20 mL), with saturated NaCl (20 mL), dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica with a 0-20% ethyl acetate-hexane gradient to afford the title compound as a clear liquid (2.5 g, 31%): 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.5 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 4.13 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −49.66; EIMS m/z 266.

Source