Boron trifluoride etherate → HCID 90253493, compound

HRID 1478760Notes

Reaction equation

HRID 1478760 reaction equation
B(F)(F)F.CCOCC.[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:12][CH2:11]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>[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C@:17]3([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[NH:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:11][CH2:12]1

Participants

6

Reactant 4

HCID 8000Boron trifluoride etherateHCID 1375192,4-Difluoro-1-iodobenzeneHCID 90253488HCID 90253488, compoundHCID 178418339Butyllithium

Product 1

HCID 90253493HCID 90253493, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Boron trifluoride diethyl etherate (5.4 g, 17.9 mmol) was added drop-wise to a solution of rel-(3aR,5S)-5-(cyclopropylmethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C69) (2.7 g, 14.9 mmol) in toluene (100 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%, 4.3 g, 17.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 6.0 mL, 14.9 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 (10 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (300 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 yellow oil. Yield: 1.85 g, 6.25 mmol, 42%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.2, 2.4 Hz, 1H), 6.80 (dt, J=10.4, 2.4 Hz, 1H), 6.31 (br s, 1H), 4.11 (dd, J=12.8, 1.6 Hz, 1H), 3.80 (d, J=12.8 Hz, 1H), 3.70 (d, J=7.2 Hz, 1H), 3.61-3.67 (m, 1H), 3.52-3.55 (m, 1H), 3.04-3.09 (m, 1H), 1.94 (dd, J=14.0, 6.8 Hz, 1H), 1.59-1.67 (m, 2H), 1.45 (q, J=15.1 Hz, 1H), 1.25 (quintet, J=6.9 Hz, 1H), 0.74-0.85 (m, 1H), 0.45-0.53 (m, 2H), 0.08-0.13 (m, 2H).

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 (10 mL) at −74° C.
  4. extractionThe resulting mixture was extracted with ethyl acetate (300 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-5a8676974d474ea7a9d2691b3e343874
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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