Potassium bis(trimethylsilyl)amide → HCID 178499339, compound

HRID 1886990Notes

Reaction equation

HRID 1886990 reaction equation
[CH3:1][C:2]([CH3:34])([CH3:33])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N:14]([CH:24]2[CH2:29][CH2:28][P:27]([O:31][CH3:32])(=[O:30])[CH2:26][CH2:25]2)[C:15]([CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C[C@H]1CC[C@H](C(Cl)=O)CC1>C1COCC1>[CH3:33][C:2]([CH3:1])([CH3:34])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N:14]([CH:24]2[CH2:29][CH2:28][P:27]([O:31][CH3:32])(=[O:30])[CH2:26][CH2:25]2)[C:15]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:6]=1

Participants

5

Reactant 3

HCID 3251421Potassium bis(trimethylsilyl)amideHCID 67971544HCID 67971544, compoundHCID 178461265HCID 178461265, compound

Product 1

HCID 178499339HCID 178499339, compoundYield 6.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Methyl 5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5phosphinan-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (420 mg, 1.1 mmol) was dissolved in 2 mL of THF and cooled to −78° C. with a dry ice-acetone bath. A solution of KHMDS (2.6 mL, 0.5 M in toluene) was added slowly, and the mixture was stirred for 5 min. Trans-4-methylcyclohexanecarbonyl chloride (210 mg, 1.3 mmol) was added dropwise and stirring was continued at −78° C. for a further 5 min. The mixture was then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl, and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10% MeOH in EtOAc: Hexanes as eluent and then further purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid), resulting in the title compound (37 mg) and recovered starting material (210 mg). MS (m/z): 508.2 [M+H]+; HPLC retention time: 4.949 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Workup

  1. stirringstirring
  2. waitwas continued at −78° C. for a further 5 min
  3. temperatureto warm to room temperature
  4. temperatureThe reaction mixture was cooled to 0° C.
  5. customquenched with saturated aqueous NH4Cl
  6. custompartitioned between water and ethyl acetate
  7. extractionThe aqueous phase was extracted with ethyl acetate
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by silica gel column chromatography
  13. customHexanes as eluent and then further purified by HPLC (Gemini column
  14. customwater, 5 min
  15. customwater, 18 min
  16. custom100% acetonitrile, 6 min
  17. additionboth solvents containing 0.1% trifluoroacetic acid),

Sources & evidence

ORD record
ord-d97d1b3237c040b688ba9dd0923e5b78
Source dataset
uspto-grants-2013_08
Patent number
US08501714B2

Reaction notes

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