Ethylbenzene → 1-[3-(2-Hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-one

HRID 2103773Notes

Reaction equation

HRID 2103773 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH3:35][C:36]([CH3:40])([CH3:39])[CH:37]=[O:38]>C1COCC1.CCCCCCC>[OH:38][CH:37]([C:36]([CH3:40])([CH3:39])[CH3:35])[CH2:17][C:8]1[C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]

Participants

7

Reactant 4

HCID 7500EthylbenzeneHCID 12417PivalaldehydeHCID 2724682Lithium diisopropylamideHCID 288262421-(5-Methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one

Product 1

HCID 578044731-[3-(2-Hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-one

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8900HeptaneSolvent

Procedure

To a solution of 0.23 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 10 mL anhydrous THF at −78° C. under nitrogen was added 0.93 mL 2 M LDA in heptane, THF, and ethylbenzene. After 15 minutes, 0.160 g trimethylacetaldehyde was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 30 minutes, evaporate the reaction mixture under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 75˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, J=9.2 Hz, 1H), 7.12 (dd, J=2.7 & 9.1 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 3.89 (s, 3H), 3.48˜3.52 (br m, 1H), 3.40 (br d, J=7.0 Hz, 1OH), 3.10˜3.16 (m, 2H), 1.43 (s, 9H), 1.10 (s, 9H). LC-MS: 4.23 min. (m/Z=245.2, 315.2, 355.2=M+Na, 259.1). A faster-eluting isomeric side-product was also isolated during purification: 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one. 1H NMR (CDCl3, 500 MHz) 7.34 (d, J=8.9 Hz, 1H), 6.87 (dd, J=2.5 & 9.0 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 4.53 (s, 1H), 3.99 (d, J=17.6 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.84 (s, 3H), 1.32 (s, 9H), 1.06 (s, 9H). LC-MS: 3.77 min. (m/Z=355.2=M+Na, 315.2). The structures of the isomers were further confirmed by COSY and NOESY spectroscopy.

Workup

  1. customRemove the cooling bath
  2. waitAfter 30 minutes
  3. customevaporate the reaction mixture under reduced pressure
  4. customto remove solvents
  5. additionDilute the residue with ether
  6. washwash with 1 M HCl (2×) and saturated brine
  7. dry with materialdry over anhydrous Na2SO4
  8. customevaporate
  9. customto give a crude product
  10. customIt was purified on RP-HPLC

Sources & evidence

ORD record
ord-033b3756bc124a288598a81a82f1eccf
Source dataset
uspto-grants-2009_08
Patent number
US07576122B2

Reaction notes

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