Hydroxylamine → HCID 22994056, compound

HRID 1167824Notes

Reaction equation

HRID 1167824 reaction equation
[C:1]([O:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:8])([CH3:4])([CH3:3])[CH3:2].NO.C([N:22](C(C)C)CC)(C)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>CCO.CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Cl:28][CH2:29][C:30]1[O:31][N:22]=[C:12]([C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([C:7](=[O:8])[NH:6][O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=2)[N:13]=1

Participants

10

Reactant 4

HCID 787HydroxylamineHCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 22994111HCID 22994111, compound

Product 1

HCID 22994056HCID 22994056, compoundYield 70.4%

Reagents, catalysts & solvents 5

HCID 142844-(Dimethylamino)pyridineCatalystHCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of 2 g (9.17 mmol, 1.0 eq.) of 3-(t-butoxycarbamoyl)benzonitrile in 25 mL of EtOH was added 0.84 mL (13.76 mmol, 1.5 eq.) of 50% aqueous solution of NH2OH. The reaction was placed in an oil bath at 80° C. and heated to 85° C. for 4 h. The solvent was removed in vacuo, and residual water was removed by azeotroping the residue with THF-toluene. Without purification, the crude hydroxyamidine (Rf=0.1 in 10% Et2O—CH2Cl2) was dissolved in 45 mL of DMF and 2.1 mL (12 mmol, 1.3 eq.) of diisopropylethyl amine and 110 mg (0.92 mmol, 0.1 eq.) of DMAP were added. The mixture was cooled to −50° C., and a solution of 0.88 mL (11 mmol, 1.2 eq.) of chloroacetyl chloride in 15 mL of CH2Cl2 (or DMF) was added dropwise, under argon. The reaction was stirred at −50° C. for 1 h, and then poured into EtOAc and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was taken up in 50 mL of dioxane and placed in an oil bath at 110° C. for about 1 h. The solvent was removed and the residue was purified on SiO2 (Et2O-hexane eluant) to yield 2 g of 5-chloromethyl-3-(3-(t-butoxy-carbamoyl)phenyl)-[1,2,4]-oxadiazole as a white solid (70% overall yield for three steps). Rf=0.9 (10% Et2O—CH2Cl2). 1H NMR (CDCl3): δ 1.5 (s, 9H), 4.75 (s, 2H), 6.62 (s br, 1H), 7.45 (dd, 1H), 7.62 (d br, 1H), 7.75 (m, 1H), 8.05 (m, 1H).

Workup

  1. customThe reaction was placed in an oil bath at 80° C.
  2. customThe solvent was removed in vacuo, and residual water
  3. customwas removed
  4. customby azeotroping the residue with THF-toluene
  5. customWithout purification
  6. dissolutionthe crude hydroxyamidine (Rf=0.1 in 10% Et2O—CH2Cl2) was dissolved in 45 mL of DMF
  7. temperatureThe mixture was cooled to −50° C.
  8. washwashed with 1N HCl and brine
  9. dry with materialThe organic layer was dried over Na2SO4
  10. customthe solvent was removed
  11. waitplaced in an oil bath at 110° C. for about 1 h
  12. customThe solvent was removed
  13. customthe residue was purified on SiO2 (Et2O-hexane eluant)
  14. customto yield

Sources & evidence

ORD record
ord-2d46b7fcd1304d0daa1cc94001b04d65
Source dataset
uspto-grants-2003_09
Patent number
US06620828B2

Reaction notes

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