Ammonium Hydroxide → (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

HRID 930288Notes

Reaction equation

HRID 930288 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-:34]=[N+]=[N-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[NH4+].[Cl-].[OH-].[NH4+].CP(C)C>C1COCC1.O.[Cu]I.CCOC(C)=O>[NH2:34][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1

Participants

11

Reactant 7

HCID 14923Ammonium HydroxideHCID 25517Ammonium Chloride2×HCID 33557Sodium AzideHCID 68983TrimethylphosphineHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 23667548Sodium AscorbateHCID 86732119(4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 71663148(4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amineYield 87.4%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8857Ethyl AcetateSolventHCID 21881883Oxolane--water (1/1)Solvent

Conditions

Temperature
80 °C

Procedure

A sealable vial was charged with (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4h, 585 mg, 1.647 mmol), sodium L-ascorbate (Acros; 32.6 mg, 0.165 mmol), sodium azide (Aldrich; 321 mg, 4.94 mmol), and copper(I) iodide (Aldrich; 94 mg, 0.494 mmol). The vial was evacuated and backfilled with Argon. EtOH (5.0 mL) and water (2.1 mL) were added, the reaction mixture purged with Argon, and then treated with N,N′-dimethyl-trans-1,2-cyclohexanediamine (Aldrich; 52.0 μL, 0.330 mmol). The reaction mixture was heated to 80° C. for 5 h and then stirred at ambient temperature for 16 h. A mixture of saturated aqueous NH4Cl and concentrated ammoniumhydroxide (5 mL; 9:1) was added, followed by EtOAc (10 mL). After 30 min, the reaction mixture was poured into a mixture of saturated aqueous NH4Cl/concentrated ammoniumhydroxide (50 mL; 9:1) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to give a brown foam, which was dissolved in THF/water (8 mL; 3:1) and treated with trimethylphosphine (Aldrich; 1.0 M in THF) (2.0 mL, 2.000 mmol). The reaction mixture was stirred for 2 days and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Gradient: 0%→10% MeOH/CH2Cl2) to give (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (419 mg, 1.439 mmol) as a white foam. MS m/z=292.1 [M+H]+. Calculated for C12H13F4N3O: 291.2

Workup

  1. customThe vial was evacuated
  2. additionEtOH (5.0 mL) and water (2.1 mL) were added
  3. customthe reaction mixture purged with Argon
  4. additionwas added
  5. waitAfter 30 min
  6. extractionextracted with EtOAc (3×50 mL)
  7. dry with materialThe combined organic extracts were dried over Na2SO4
  8. concentrationconcentrated
  9. customto give a brown foam, which
  10. stirringThe reaction mixture was stirred for 2 days
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was purified by flash chromatography on silica gel (Gradient: 0%→10% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-e8f097bc9b1647c5a732f69a4e0f31c2
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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