1,8-Diazabicyclo(5.4.0)undec-7-ene → (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one

HRID 333892Notes

Reaction equation

HRID 333892 reaction equation
Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:25]=[C:26]=[O:27])[CH3:24])=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:23]([N:25]2[CH2:2][CH2:3][C@:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])[CH3:24])=[CH:21][CH:22]=1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 75688421-bromo-4-[(1S)-1-isocyanatoethyl]benzeneHCID 595323881-Chlor-5-methyl-3-phenylhex-5-en-3-ol2×

Product 1

HCID 46830455(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-oneYield 54.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
75 °C

Procedure

To a dried 10 L jacketed reactor under a nitrogen atmosphere was charged 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (167 g, 81.7 wt %, 610 mmol, 1.00 equiv), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, 93.7 wt %, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv). The resulting solution was agitated and refluxed (Tint=67-69° C., Text=75° C.) for 19 h, at which point HPLC analysis indicated ˜1A % (220 nm) of the 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol remained. The dark solution was cooled to Tint=20-25° C. Two liters of tetrahydrofuran were removed by distillation under reduced pressure. The remaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0 L of hexanes. The resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note: the wash is slightly exothermic). The aqueous solution was cut and the remaining organic solution was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was subjected to flash silica chromatography (5-30% ethyl acetate/hexanes, 1.74 kg of silica) to produce 137.8 g of material (59 wt %, 3.1:1 diastereomeric ratio favoring the desired diastereomer

Workup

  1. temperatureThe dark solution was cooled to Tint=20-25° C
  2. customTwo liters of tetrahydrofuran were removed by distillation under reduced pressure
  3. additionThe remaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0 L of hexanes
  4. washThe resulting solution was washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note
  5. dry with materialthe remaining organic solution was dried with anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to an oil via reduced pressure

Sources & evidence

ORD record
ord-81d34cd0aa1e4f2a83830261b4701a84
Source dataset
uspto-grants-2014_11
Patent number
US08883778B2

Reaction notes

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