Magnesium → (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2'-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate

HRID 1043411Notes

Reaction equation

HRID 1043411 reaction equation
[Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])=[CH:5][CH:4]=1.[O:17]=[C:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1>C1COCC1.C1(C)C=CC=CC=1>[OH:17][C@:18]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:15]=[CH2:16])=[CH:5][CH:4]=2)[CH2:22][N:21]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[O:24])[C@H:20]([C:32]([O:34][CH3:35])=[O:33])[CH2:19]1

Participants

6

Reactant 3

HCID 5462224Magnesium3×HCID 59266363(S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate2×HCID 592664864'-Bromo-2-vinylbiphenyl2×

Product 1

HCID 59266527(2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2'-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylateYield 30.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Magnesium (0.110 g, 4.58 mmol) turnings were stirred in a round bottom flask under nitrogen for 30 min. to cause scratching of the surface of the magnesium. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-2-vinylbiphenyl (Intermediate 1, 1.13 g, 4.36 mmol) in THF (30 mL), was added dropwise at reflux with vigorous stirring. The Grignard solution (40 mL) was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (Intermediate 2, 1.0 g, 3.53 mmol) in toluene (30 mL) at 0° C. and stirred for 1 hr and then quenched with a saturated NH4Cl solution. The aqueous layer was extracted with DCM. The combined organics were washed with brine and dried over MgSO4, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-33% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (0.5 g, 30% yield) as a yellow oil. LCMS: rt=1.92 min. [M+Na]+=490; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 9H) 0.88-1.14 (m, 2H) 2.38-2.50 (m, 1H) 2.74 (dd, J=13.58, 10.22 Hz, 1H) 3.89 (d, J=11.60 Hz, 2H) 3.76-3.84 (m, 1H) 3.86 (s, 3H) 4.00 (dd, 1H) 4.23 (s, 1H) 4.24-4.28 (m, 1H) 4.55-4.66 (m, 1H) 5.20 (dd, J=10.9, 1.22 Hz, 1H) 5.71 (dd, J=17.55, 1.07 Hz, 1H) 6.70 (dd, J=17.40, 10.99 Hz, 1H) 7.28 (dd, 1H) 7.34 (dd, J=7.17, 1.68 Hz, 1H) 7.37 (d, J=8.55 Hz, 2H) 7.54 (d, J=8.24 Hz, 2H) 7.65 (d, J=7.32 Hz, 1H).

Workup

  1. temperatureat reflux with vigorous stirring
  2. stirringstirred for 1 hr
  3. customquenched with a saturated NH4Cl solution
  4. extractionThe aqueous layer was extracted with DCM
  5. washThe combined organics were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customto give crude material
  10. customThe crude material was purified by flash chromatography on the Biotage (20-33% EtOAc:Hex)

Sources & evidence

ORD record
ord-21487d3c9a1140b1882e503be5463fe5
Source dataset
uspto-grants-2013_10
Patent number
US08563505B2

Reaction notes

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