Ethyl isobutyrate → 3-{4-[4-(2-Ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl ester

HRID 2057197Notes

Reaction equation

HRID 2057197 reaction equation
[C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].CN1[C:15](=[O:16])N(C)CCC1.[Li+].CC([N-][CH:23]([CH3:25])[CH3:24])C.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=2)=[O:35])=[CH:30][CH:29]=1.C1C[O:47][CH2:46][CH2:45]1>>[CH2:46]([O:47][C:15](=[O:16])[C:23]([CH3:24])([CH3:25])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:35])[C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:4])[CH3:3])=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)[CH3:45]

Participants

6

Reactant 5

HCID 7342Ethyl isobutyrateHCID 8028Tetrahydrofuran2×HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-HCID 23039244,4'-Bis(bromomethyl)benzophenoneHCID 2724682Lithium diisopropylamide

Product 1

HCID 666170323-{4-[4-(2-Ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethyl-propionic acid ethyl esterYield 34%

Procedure

Under Ar atmosphere, to a solution of ethyl isobutyrate (18.2 g, 156.6 mmol) and DMPU (1 mL) in THF (30 mL) was added LDA (80 mL, 2 M in heptanes, 160 mmol) at −78° C. The mixture was stirred for 30 min. A solution of bis-(4-bromomethylphenyl)-methanone (21.1 g, 57.3 mmol) in THF (100 mL) was added dropwise. The reaction mixture was allowed to stir overnight, gradually warming to room temperature. Most of the THF (120 mL) was removed under reduced presure. The mixture was hydrolyzed with 6 N aqueous HCl (30 mL), water (170 g), and saturated NH4Cl solution (200 mL). The solution was extracted with ethyl acetate (200 mL, 2×100 mL). The organic layers were washed with half-saturated NaCl solution (100 mL), dried over MgSO4, and concentrated under vacuum to give a crude oil (35.8 g). Purification by column chromatography on silica (800 g) using hexanes/ethyl acetate (10:1) as eluent afforded 3-{4-[4-(2-ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethylpropionic acid ethyl ester (8.50 g, 34%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.73 (d, 4H, J=8.1 Hz), 7.26 (d, 4H, J=8.1 Hz), 4.19-4.11 (m, 4H), 2.97 (s, 4H), 1.29-1.15 (m, 18H). 13C NMR (75 MHz, CDCl3=77.00 ppm): δ (ppm): 195.8, 176.8, 142.9, 135.8, 129.9, 129.7, 60.4, 46.0, 43.4, 24.8, 14.1. HRMS (LSIMS, nba): Calcd for C27H35O5 (M+H): 439.2484, found: 439.2487.

Workup

  1. stirringto stir overnight
  2. customMost of the THF (120 mL) was removed
  3. extractionThe solution was extracted with ethyl acetate (200 mL, 2×100 mL)
  4. washThe organic layers were washed with half-saturated NaCl solution (100 mL)
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated under vacuum
  7. customto give a crude oil (35.8 g)
  8. customPurification by column chromatography on silica (800 g)

Sources & evidence

ORD record
ord-d43305b2183e4dfaa8509d2be4290e07
Source dataset
uspto-grants-2008_02
Patent number
US07335799B2

Reaction notes

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