Chloromethyl ethyl ether → Methyl(1R,4S)-4-[(tert-Butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopent-2-ene-1-carboxylate

HRID 270607Notes

Reaction equation

HRID 270607 reaction equation
C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl[CH2:29][O:30][CH2:31][CH3:32]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][O:30][CH2:31][CH3:32])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 18523Chloromethyl ethyl etherHCID 2733832Lithium HexamethyldisilazideHCID 10610130(1R,4S)-methyl 4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylate

Product 1

HCID 57938729Methyl(1R,4S)-4-[(tert-Butoxycarbonyl)amino]-1-(ethoxymethyl)cyclopent-2-ene-1-carboxylateYield 662%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (36.7 mL, 36.7 mmmol) was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (4.00 g, 1.66 mmol) in tetrahydrofuran (6.0 mL) at −78° C. The resulting light brown solution was stirred at −78° C. for 30 min before (chloromethoxy)ethane (1.88 g, 19.9 mol) was added in one portion. The mixture was stirred at −78° C. for 1 h and then kept in a freezer reading at −25° C. overnight. The reaction was then quenched with saturated NH4Cl (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (0 to 15% EtOAC in hexanes) to provide the desired product (3.29 g, 66%) as a cis/trans (3:2) mixture based on the analysis on reverse phase HPLC. MS calculated for C15H26NO5: (M+H) 300.2; found 200.2 (M+H-Boc).

Workup

  1. additionwas added in one portion
  2. waitkept in a freezer reading at −25° C. overnight
  3. customThe reaction was then quenched with saturated NH4Cl (50 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with CH2Cl2 three times
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custompurified by flash chromatography (0 to 15% EtOAC in hexanes)

Sources & evidence

ORD record
ord-b4fcc16f62234ca69e7e6807016ce800
Source dataset
uspto-grants-2008_11
Patent number
US07449467B2

Reaction notes

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