Hydroxylamine → Ethyl 2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate

HRID 1372216Notes

Reaction equation

HRID 1372216 reaction equation
Cl[CH2:2][CH2:3][O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[Na+].[I-].[NH2:12][OH:13].[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:14]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:13][N:12]2[C:6]([C:5]([CH3:9])([CH3:8])[O:4][CH2:3][CH2:2]2)=[N:7]1)[CH3:20]

Participants

7

Reactant 4

HCID 787HydroxylamineHCID 5238Sodium IodideHCID 69803Diethyl acetylenedicarboxylateHCID 210697862-(2-Chloroethoxy)-2-methylpropanenitrile

Product 1

HCID 21069948Ethyl 2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylateYield 48.6%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of intermediate 23, 2-(2-chloroethoxy)-2-methylpropanenitrile (14.7 g, 0.10 mole) and NaI (1.5 g, 10 mmol) in ethanol (50 mL) was added an aqueous solution (50%) of hydroxylamine (18.4 g, 0.30 mole) resulting in an exothermic reaction. Following this the reaction mixture was heated at 80° C. for 2 h. Upon cooling to room temperature the solvent was removed. The resulting residue was dissolved in 1:1 ethanol/H2O (100 mL) and cooled in an ice bath. To this was added diethyl acetylenedicarboxylate (17.6 mL, 0.110 mole) over 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. Following this, it was diluted with ethyl acetate (250 mL), washed with H2O (2×100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the crude product as a yellow oil. Flash chromatography on a silica gel column, eluting with 20–40% ethyl acetate/Hexanes, provided the title compound as a viscous pale yellow oil (15.29 g, 48.6% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 4.35–4.28 (2H, m), 4.18–4.12 (2H, m), 3.60–3.56 (1H, m), 3.51–3.47 (1H, m), 3.30 (1H, d, J=16.2 Hz), 2.94 (1H, d, J=16.2 Hz), 1.52 (3H, s), 1.51 (3H, s), 1.29 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.0 Hz). LCMS (M+H) calcd for C14H23N2O7: 315.16. found: 315.33.

Workup

  1. customresulting in an exothermic reaction
  2. temperatureUpon cooling to room temperature the solvent
  3. customwas removed
  4. dissolutionThe resulting residue was dissolved in 1:1 ethanol/H2O (100 mL)
  5. temperaturecooled in an ice bath
  6. temperatureto warm to room temperature
  7. washwashed with H2O (2×100 mL), brine (50 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give the crude product as a yellow oil
  12. washFlash chromatography on a silica gel column, eluting with 20–40% ethyl acetate/Hexanes

Sources & evidence

ORD record
ord-e4123ddae9b84a8fb69f44ef5c77224e
Source dataset
uspto-grants-2007_01
Patent number
US07157447B2

Reaction notes

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