Ammonia → (R)-3-(N,N-Dibenzylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran

HRID 1738311Notes

Reaction equation

HRID 1738311 reaction equation
Br[C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][C:6]=2[C:5]([O:27][CH3:28])=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:44])(=O)=O)=CC=1.[NH4+].[Cl-].NO.Cl.C([O-])([O-])=O.[Na+].[Na+].N>C1COCC1.O>[CH2:13]([N:12]([C@@H:8]1[CH2:7][C:6]2[C:5]([O:27][CH3:28])=[CH:4][CH:3]=[C:2]([F:44])[C:11]=2[O:10][CH2:9]1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1

Participants

11

Reactant 8

HCID 222AmmoniaHCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 10340Sodium CarbonateHCID 25517Ammonium ChlorideHCID 588007N-FluorobenzenesulfonimideHCID 54247483HCID 54247483, compoundHCID 178418339Butyllithium

Product 1

HCID 20640362(R)-3-(N,N-Dibenzylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyranYield 40.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

(R)-8-Bromo-3-(N,N-dibenzylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (4.35 g, 9.9 mmol) was dissolved in 45 mL of anhydrous THF and cooled to -78° C. To this was a 1.6M n-BuLi solution (6.8 mL, 10.9 mmol) added dropwise and the mixture was allowed to stir at -78° C. for 1 h. N-Fluorobenzenesulfonimide (3.8 g, 11.9 mmol), dissolved in 30 mL anhydrous THF, was added dropwise over 45 min and allowed to stir at -78° C. for 1 h. The reaction was stopped by adding 3 mL saturated NH4Cl followed by 9 mL of a solution comprised of 2 g of NH2OH×HCl and 8 g of Na2CO3 in 100 mL of H2O and allowing the reaction to warm to room temperature. A 2M NH3 solution was added and the reaction was extracted twice with ether, treated with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give the crude product. Purification of the 8-fluoro (desired) from the 8-hydrogen (15 %) compound was carried out by a crude chromatography (eluent: 25% CH2Cl2 /hexane) to give 1.78 g. The crude product was rechromatographed on silica (eluent: 3% acetone/hexane) to give 1.50 g (40% yield) of the title compound as a clear oil. [α]21D =-112.1° (C=0.1, CHCl3). GC-MS (70 eV) M=377 (37%).

Workup

  1. additionadded dropwise
  2. additionwas added dropwise over 45 min
  3. stirringto stir at -78° C. for 1 h
  4. customthe reaction
  5. temperatureto warm to room temperature
  6. extractionthe reaction was extracted twice with ether
  7. additiontreated with brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customto give the crude product
  12. customPurification of the 8-fluoro (desired) from the 8-hydrogen (15 %) compound
  13. customto give 1.78 g
  14. customThe crude product was rechromatographed on silica (eluent: 3% acetone/hexane)

Sources & evidence

ORD record
ord-6eb621d260c94c578a0198680791f9e3
Source dataset
uspto-grants-1999_10
Patent number
US05962514

Reaction notes

Loading…