Boron trifluoride etherate → HCID 90253576, compound

HRID 1478749Notes

Reaction equation

HRID 1478749 reaction equation
B(F)(F)F.CCOCC.[CH3:10][C:11]1([C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:13][CH2:12]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@:17]12[CH2:21][O:22][C@@H:14]([C:11]3([CH3:10])[CH2:12][CH2:13]3)[CH2:15][C@H:16]1[CH2:20][O:19][NH:18]2

Participants

6

Reactant 4

HCID 8000Boron trifluoride etherateHCID 1375192,4-Difluoro-1-iodobenzeneHCID 90253578HCID 90253578, compoundHCID 178418339Butyllithium

Product 1

HCID 90253576HCID 90253576, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Boron trifluoride diethyl etherate (7.86 g, 25.9 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-(1-methylcyclopropyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C56) (4.255 g, 23.5 mmol) in toluene (500 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 6.22 g, 25.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 9.9 mL, 24.8 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 3.2 g, 10.8 mmol, 46%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.4, 2.4 Hz, 1H), 6.78 (ddd, J=11.6, 8.8, 2.4 Hz, 1H), 6.28 (br s, 1H), 4.04 (dd, J=12.4, 1.6 Hz, 1H), 3.82 (d, J=12.8 Hz, 1H), 3.72 (d, J=6.8 Hz, 1H), 3.53 (dd, J=6.8, 4.8 Hz, 1H), 3.01-3.06 (m, 1H), 2.95 (d, J=12.0 Hz, 1H), 1.83 (dd, J=13.2, 6.0 Hz, 1H), 1.62 (q, J=12.4 Hz, 1H), 1.09 (s, 3H), 0.52-0.56 (m, 1H), 0.43-0.48 (m, 1H), 0.36-0.41 (m, 1H), 0.28-0.33 (m, 1H).

Workup

  1. temperatureWhile the reaction temperature was maintained below −73° C.
  2. stirringThe reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours
  3. customwas quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C.
  4. extractionThe resulting mixture was extracted with ethyl acetate (400 mL)
  5. extractionthe aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL)
  6. dry with materialthe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-639ac767886b4711b62cb13f79900669
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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