Chloromethyl Methyl Ether → (S)-4-Isopropyl-3-((S)-2-methoxymethyl-2-methyl-but-3-enoyl)-oxazolidin-2-one

HRID 2176277Notes

Reaction equation

HRID 2176277 reaction equation
[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])/[C:11](/[CH3:14])=[CH:12]/[CH3:13])([CH3:3])[CH3:2].[O:16]1[CH2:20]CN[C:17]1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].COCCl.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])[C@@:11]([CH2:17][O:16][CH3:20])([CH3:14])[CH:12]=[CH2:13])([CH3:3])[CH3:2]

Participants

7

Reactant 5

HCID 7864Chloromethyl Methyl EtherHCID 25517Ammonium ChlorideHCID 739492-OxazolidinoneHCID 2724254Sodium bis(trimethylsilyl)amideHCID 11735975(S)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one

Product 1

HCID 86706122(S)-4-Isopropyl-3-((S)-2-methoxymethyl-2-methyl-but-3-enoyl)-oxazolidin-2-oneYield 48%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of (S)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one (prepared according to the method reported in Example 29c but using the opposite enantiomer of the oxazolidinone), (4.44 g, 21 mmol), in anhydrous toluene (40 mL) under nitrogen at −78° C. was added dropwise a solution of Sodium bis(trimethylsily)amide in toluene (0.6 M, 54 mL, 32 mmol). When addition was completed, the reaction mixture was left to stir at −78° C. for another minutes. Chloromethyl methyl ether (3.38 g, 42 mmol) was slowly added. Stirring was maintained at −60° C. for 30 minutes and then for 1 h as the temperature was allowed to rise to 0° C. Saturated ammonium chloride solution (230 mL) was added and the mixture was left to stir at room temperature for 10 minutes. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The crude residue was purified by silica gel chromatography using a Biotage KP-Sil 100 g cartridge eluting with a gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to give the title product (2.55 g, 48%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.80-1.00 (m, 6H), 1.50 (s, 3H), 2.25-2.45 (m, 1H), 3.35 (s, 3H), 3.46 (d, J=8.7 Hz, 1H), 4.16-4.23 (m, 2H), 4.28 (app t, J=8.2 Hz, 1H), 4.45-4.60 (m, 1H), 5.01 (d, J=17.6 Hz, 1H), 5.12 (d, J=10.7 Hz, 1H), 6.19 (dd, J=17.6, 10.7 Hz, 1H). LCMS (m/z) 255.3 [M+H], Tr=2.58 min.

Workup

  1. customat −78° C.
  2. additionWhen addition
  3. waitthe reaction mixture was left
  4. stirringStirring
  5. temperaturewas maintained at −60° C. for 30 minutes
  6. customto rise to 0° C
  7. waitthe mixture was left
  8. stirringto stir at room temperature for 10 minutes
  9. extractionThe aqueous layer was extracted with ethyl acetate (2×)
  10. washthe combined organic layers were washed with brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. filtrationfiltered
  13. customThe filtrate was evaporated
  14. customThe crude residue was purified by silica gel chromatography
  15. washeluting with a gradient of iso-hexanes/ethyl acetate 1:0 to 9:1

Sources & evidence

ORD record
ord-810923b8a6cf4c628b814ea430db3593
Source dataset
uspto-grants-2015_06
Patent number
US09062092B2

Reaction notes

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