Imidazole → Methyl((1r,2r,3r,5s)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-oxabicyclo[3.1.0]hex-2-yl)fluoroacetate

HRID 507818Notes

Reaction equation

HRID 507818 reaction equation
[F:1][CH:2]([C@H:7]1[C@H:12]([OH:13])[CH2:11][C@H:10]2[C@@H:8]1[O:9]2)[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C@H:7]1[C@H:12]([O:13][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24])[CH2:11][C@H:10]2[C@@H:8]1[O:9]2)[F:1]

Participants

5

Reactant 3

HCID 795ImidazoleHCID 28928tert-Butyldimethylsilyl chlorideHCID 59434307Methyl fluoro[(1R,2S,3R,5S)-3-hydroxy-6-oxabicyclo[3.1.0]hex-2-yl]acetate

Product 1

HCID 59434305Methyl((1r,2r,3r,5s)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-oxabicyclo[3.1.0]hex-2-yl)fluoroacetate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
5 °C

Procedure

To a solution of epoxy alcohol 3 (1.60 kg, 8.40 mol) and DMF (3.40 L) was added imidazole (1.26 kg, 18.5 mol) at 10° C. TBSCl (1.52 kg, 10.1 mol) was added to the reaction mixture while maintaining the batch temperature below 8° C. The resulting solution was stirred at 5° C. for 10 min, then allowed to warm to 20° C. over 30 min and stirred for 2 h at the same temperature. The consumption of the starting alcohol was monitored by GC, and the reaction mixture was diluted with cold toluene (17.0 L, 5° C.). The resulting mixture was washed with H2O (5.67 L), saturated aqueous NaHCO3 (5.67 L), H2O (5.67 L×2), and brine (5.67 L). Assay of the organic solution indicated 4. Concentration of the solution gave 4 as yellow liquid, which was used for the next step without further purification. Analytically pure sample was obtained by flash silica gel column chromatography (hexanes/MTBE) as colorless crystals: mp 28-30° C.; 1H NMR (400 MHz, CDCl3) δ 5.00 (dd, J=48.2, 3.5 Hz, 1H), 4.45 (m, 1H), 3.85 (s, 3H), 3.51 (m, 1H), 3.42 (m, 1H), 2.64-2.52 (dm, J=34.5 Hz, 1H), 2.14 (m, 1H), 1.91 (m, 1H), 0.88 (s, 9H), 0.054 (s, 3H), and 0.051 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.8 (d, J=24.1 Hz), 88.3 (d, J=186.1 Hz), 75.4 (d, J=1.6 Hz), 58.3, 57.2 (d, J=7.2 Hz), 52.8 (d, J=19.3 Hz), 52.7, 38.3, 25.9, 18.0, −4.5, and −4.7; 19F NMR (376 MHz, CDCl3) δ −199.9 (dd, J=48.2, 34.5 Hz); LRMS m/z 305 (M+1), 121 (base peak); [α]D25=−27 (c 1.0, CHCl3).

Workup

  1. temperaturewhile maintaining the batch temperature below 8° C
  2. temperatureto warm to 20° C. over 30 min
  3. stirringstirred for 2 h at the same temperature
  4. customThe consumption of the starting alcohol
  5. additionthe reaction mixture was diluted with cold toluene (17.0 L, 5° C.)
  6. washThe resulting mixture was washed with H2O (5.67 L), saturated aqueous NaHCO3 (5.67 L), H2O (5.67 L×2), and brine (5.67 L)

Sources & evidence

ORD record
ord-139f939e5b6b43358e749fe790fc9c39
Source dataset
uspto-grants-2010_08
Patent number
US07786314B2

Reaction notes

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