Nitrogen → 3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)4-hydroxy-phenyl]-acrylic acid tert-butyl ester

HRID 1181051Notes

Reaction equation

HRID 1181051 reaction equation
Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][Si](C(C)(C)C)(C)C)=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].C(#N)CC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.N#N.[C:65]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])(=[O:68])[CH:66]=[CH2:67].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:70]([O:69][C:65](=[O:68])[CH:66]=[CH:67][C:2]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])([CH3:73])([CH3:72])[CH3:71]

Participants

9

Reactant 7

HCID 947NitrogenHCID 7854PropionitrileHCID 15458tert-Butyl acrylateHCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium Fluoride2×HCID 179843932-[2-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzyl]-isoindole-1,3-dione

Product 1

HCID 687431663-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)4-hydroxy-phenyl]-acrylic acid tert-butyl esterYield 87%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
95 °C

Procedure

A 12 L flask was charged with 2-[2-bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzyl]-isoindole-1,3-dione (461 g, 1.03 mol), propionitrile (7 L), tri-ortho-tolyl phosphine (76.0 g, 0.250 mol) and diisopropyl ethyl amine (365 mL, 2.10 mol). The reaction mixture was degassed/purged with N2 (3×), and tert-butyl acrylate (465 mL, 3.17 mol) was added. After degassing/purging one time, palladium (II) acetate (28.0 g, 0.125 mol) was added. The stirred mixture was degassed/purged with N2 three times and heated to 95° C. for 20 h. The mixture was filtered through a hyflo cake, washed with acetonitrile, and concentrated to a brown oil (841 g). The residue was dissolved in THF (3.5 L), and tetrabutylammonium fluoride (TBAF, 650 mL, 0.65 mol, 1M in THF) was added. After 1 h, additional TBAF (95 mL) was added. The mixture was rotated on the rotary evaporator for 10 min and was concentrated to crude product (987 g). This material was purified by silica gel chromatography (toluene/ethyl acetate, 100/0 to 75/25) to give the title compound (340 g, 86.8%).

Workup

  1. additionwas added
  2. additionwas added
  3. customThe stirred mixture was degassed/purged with N2 three times
  4. filtrationThe mixture was filtered through a hyflo cake
  5. washwashed with acetonitrile
  6. concentrationconcentrated to a brown oil (841 g)
  7. dissolutionThe residue was dissolved in THF (3.5 L)
  8. customThe mixture was rotated on the rotary evaporator for 10 min
  9. concentrationwas concentrated to crude product (987 g)
  10. customThis material was purified by silica gel chromatography (toluene/ethyl acetate, 100/0 to 75/25)

Sources & evidence

ORD record
ord-439de2b55acf4ab4a8cd76b5c1cba243
Source dataset
uspto-grants-2007_10
Patent number
US07282501B2

Reaction notes

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