tert-Butyl hydroperoxide → [5-(3-Bromo-phenyl)-6-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester

HRID 81528Notes

Reaction equation

HRID 81528 reaction equation
BrC1C=C(C2([CH2:15][F:16])NC(=S)COC2)C=CC=1.C(OO)(C)(C)C.[NH4+].[OH-].[Br:25][C:26]1[CH:27]=[C:28]([C:32]2(CF)[CH2:37][O:36][CH2:35][C:34]([NH2:38])=[N:33]2)[CH:29]=[CH:30][CH:31]=1.CCN(C(C)C)C(C)C.[CH3:50][C:51]([O:54][C:55]([O:57]C(OC(C)(C)C)=O)=O)([CH3:53])[CH3:52]>N.CO.ClCCl>[C:51]([O:54][C:55](=[O:57])[NH:38][C:34]1[CH2:35][O:36][CH:37]([CH2:15][F:16])[CH:32]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Br:25])[CH:27]=2)[N:33]=1)([CH3:53])([CH3:52])[CH3:50]

Participants

9

Reactant 6

HCID 6410tert-Butyl hydroperoxideHCID 14923Ammonium HydroxideHCID 81531DiisopropylethylamineHCID 90495Di-tert-butyl dicarbonateHCID 66666031HCID 66666031, compoundHCID 86650251HCID 86650251, compound

Product 1

HCID 86716529[5-(3-Bromo-phenyl)-6-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 21705897Ammonia methanolSolvent

Procedure

To a solution of 5-(3-bromo-phenyl)-5-fluoromethyl-morpholine-3-thione (200 mg, 0.658 mmol) in 5 ml of 7M NH3/MeOH were added t-butyl hydroperoxide (80%, 0.818 ml, 6.58 mmol) and then 1.7 ml of 25% aqueous NH4OH. After 2 h, the mixture was quenched with a saturated aqueous solution of Na2S2O3 and extracted with EtOAc. The extract was washed with brine, dried with sodium sulfate and evaporated. The crude 5-(3-bromo-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (189 mg, 0.658 mmol) was dissolved in 4 ml of dichloromethane. The solution was treated with DIPEA (0.172 ml, 0.987 mmol) and Boc2O (187 mg, 0.855 mmol). After 14 h, the mixture was diluted with dichloromethane and washed with water, 1N HCl and brine. The organic phase was dried with sodium sulfate and evaporated. The residue was chromatographed on silica gel (cyclohexane/EtOAc=6:1) to yield the title compound. TLC (hexane/EtOAc=6:1): Rf=0.20; HPLC: RtH1=2.380 min; 1H-NMR (400 MHz, CDCl3): 7.56-6.98 (m, 4H; broad signals due to rotamers), 4.80-3.60 (m, 6H), 1.42 (br, 9H); MS: 387, 389 [(M+H)+].

Workup

  1. customthe mixture was quenched with a saturated aqueous solution of Na2S2O3
  2. extractionextracted with EtOAc
  3. washThe extract was washed with brine
  4. dry with materialdried with sodium sulfate
  5. customevaporated
  6. waitAfter 14 h
  7. washwashed with water, 1N HCl and brine
  8. dry with materialThe organic phase was dried with sodium sulfate
  9. customevaporated
  10. customThe residue was chromatographed on silica gel (cyclohexane/EtOAc=6:1)

Sources & evidence

ORD record
ord-6de07e70ae984ff7bb1841da8eab8814
Source dataset
uspto-grants-2014_09
Patent number
US08846658B2

Reaction notes

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