Lithium Hexamethyldisilazide → (4R)-2-oxo-N-[(1R)-1-phenylpropyl]-4-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxamide

HRID 321941

Reaction equation

HRID 321941 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][C@@H:9]1[NH:12][C:11](=[O:13])[CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24]1([C@H:30]([N:33]=[C:34]=[O:35])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([C@H:30]([NH:33][C:34]([N:12]2[C@@H:9]([CH2:8][S:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:10][C:11]2=[O:13])=[O:35])[CH2:31][CH3:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 7018288(R)-(+)-1-Phenylpropyl isocyanateHCID 543962814(R)-(pyrimidin-2-ylsulfanylmethyl)azetidin-2-one

Product 1

HCID 479658(4R)-2-oxo-N-[(1R)-1-phenylpropyl]-4-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxamideYield 67%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4(R)-(pyrimidin-2-ylsulfanyl-methyl)azetidin-2-one (61.5 mg, 0.315 mmol) in THF (3 mL) at 0° was added dropwise LiHMDS (1M/THF) (0.33 mL, 0.331 mmol). After the reaction mixture was stirred 15 min at 0°, then cooled to −78°, 1(R)-phenylpropyl isocyanate (example 1) (0.53M/toluene, 0.63 mL, 0.315 mmol) was added dropwise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and evaporated. The product was purified by flash chromatography (SiO2, 30% EtOAc/hexane) to give 2-oxo-4(R)-(pyrimidin-2-ylsulfanylmethyl)azetidine-1-carboxylic acid (1(R)-phenylpropyl)amide (75 mg, 67% yield) as a viscous gum. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 2H), 7.29-7.17 (m, 5H), 6.94 (t, J=4.8 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H) 4.71 (q, J=7.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.03 (dd, J=14.2, 3.3 Hz, 1H), 3.39 (dd, J=14.2, 8.3 Hz, 1H), 3.03 (dd, J=16.0, 5.6 Hz, 1H), 2.89 (dd, J=16.0, 3.0 Hz, 1H), 1.83-1.75 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); IR (neat) υ 1758, 1692 cm−1; FAB MS m/z 357.3 (MH+); HRMS calcd. for C18H21N4O2S (MH+) 357.1385, found 357.1379.

Workup

  1. temperaturecooled to −78°
  2. stirringstirred for 1.5 h
  3. customThe reaction mixture was quenched with H2O
  4. additiondiluted with EtOAc
  5. washThe organic phase was washed with H2O and brine
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customThe product was purified by flash chromatography (SiO2, 30% EtOAc/hexane)

Sources & evidence

ORD record
ord-342bc74d26cd4e2f9a704bedb14a9ea4
Source dataset
uspto-grants-2001_04
Patent number
US06211170B1

Linked notes

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