Citric Acid → (S)-8-Fluoro-6-methyl-5,6-dihydrophenanthridine

HRID 2224632Notes

Reaction equation

HRID 2224632 reaction equation
[BH4-].[Li+].Cl[Si](C)(C)C.[F:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([CH3:23])[N:13]=[C:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O1CCCC1.CO.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][CH:22]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:13][C@H:12]2[CH3:23]

Participants

9

Reactant 4

HCID 311Citric Acid2×HCID 6397ChlorotrimethylsilaneHCID 4148881Lithium borohydrideHCID 224823738-Fluoro-6-methylphenanthridine

Product 1

HCID 58597405(S)-8-Fluoro-6-methyl-5,6-dihydrophenanthridineYield 95.3%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred suspension of lithium borohydride (8.25 g, 0.378 mole) in a mixture of toluene (94.7 niL) and tetrahydrofuran (9.46 mL) kept under nitrogen and at 0° C. was added dropwise chlorotrimethylsilane (96.1 nmL). Additional tetrahydrofuran (30 mL) and toluene (105 mL) were added to rinse the glassware. (R)-2-methyl-CBS-oxazaborolidine (56.8 mL) was added dropwise at room temperature. The mixture was cooled to 0° C. and solid 8-fluoro-6-methylphenanthridine (40 g, 0.189 mole) was added in two portions over a 10 minute and 5 minute period, respectively. The cooling bath was removed, the flask walls rinsed with toluene (60 mL) and the brown slurry was stirred at room temperature. Aliquots were taken at regular intervals to monitor the progress of the reaction. After 8 days the conversion reached 97% . The reaction mixture was cooled to 0° C., treated dropwise with 10% aqueous citric acid (100 mL) under vigorous stirring to control foaming. Ethyl acetate was added (800 mL) followed by more 10% aqueous citric acid (300 mL) and then methanol (300 mL) to redissolve the precipitate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness to provide 38.4 g (95% yield) of the title compound.

Workup

  1. customkept under nitrogen and at 0° C.
  2. washto rinse the glassware
  3. addition(R)-2-methyl-CBS-oxazaborolidine (56.8 mL) was added dropwise at room temperature
  4. customThe cooling bath was removed
  5. washthe flask walls rinsed with toluene (60 mL)
  6. customthe progress of the reaction
  7. temperatureThe reaction mixture was cooled to 0° C.
  8. stirringunder vigorous stirring
  9. customThe layers were separated
  10. washthe organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL)
  11. dry with materialdried over anhydrous sodium sulfate
  12. customevaporated to dryness

Sources & evidence

ORD record
ord-a922eb9fc9604dfd9414f42e17b081bf
Source dataset
uspto-grants-2008_05
Patent number
US07378427B2

Reaction notes

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