Cornforth reagent → HCID 10195869, compound

HRID 1270212Notes

Reaction equation

HRID 1270212 reaction equation
[C:1]([C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)#[CH:2].C([Li])CCC.[CH3:23][O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([CH:36]=[O:37])=[CH:30][C:29]=1[O:38][CH3:39].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[CH3:23][O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31]([C:36](=[O:37])[C:2]#[C:1][C:3]2[CH:8]=[C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[C:6]([O:14][CH3:15])=[CH:5][C:4]=2[O:16][CH3:17])=[CH:30][C:29]=1[O:38][CH3:39]

Participants

6

Reactant 4

HCID 2724130Cornforth reagentHCID 18449299HCID 18449299, compoundHCID 43516604HCID 43516604, compoundHCID 178418339Butyllithium

Product 1

HCID 10195869HCID 10195869, compoundYield 49.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Ex-3: A solution of 2-(5-ethynyl-2,4-dimethoxy-phenyl)-thiophene (1.0 g, 4.09 mmol) from Ex-1B in THF (35 mL) was cooled to −78° C. n-Butyllithium (4.62 mmol, 1.85 mL of a 2.5 M solution in hexanes) was added over 15 min while maintaining an internal temperature below −50° C. After aging for 15 min at −78° C., the reaction was transferred via cannula over 5 min to a cold (−78° C.) solution of (4-formyl-2,6-dimethoxy-phenoxy)-acetic acid methyl ester (1.15 g, 4.52 mmol) from Ex-3A in THF (25 mL). The resulting solution was slowly warmed to room temperature and then quenched with a saturated NH4Cl solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure The resulting crude {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester was dissolved in dichloromethane (50 mL), charged with pyridinium dichromate (3.00 g, 7.97 mmol) and aged at room temperature under nitrogen for 2.5 h. The reaction was then filtered through a pad of celite using additional dichloromethane and then ethyl acetate. The combined organic was concentrated under reduced pressure. Silica gel chromatography (ethyl acetate/hexane, 3:2) gave 1.0 g (49%) of the desired {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester as a yellow solid, m.p. 153–155° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.60 (s, 2H), 7.41 (dd, 1H, J=3.6 and 1.5 Hz), 7.35 (dd, 1H, J=5.3 and 1.5 Hz), 7.09 (dd, 1H, J=5.3 and 3.6 Hz), 6.54 (s, 1H), 4.77 (s, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.97 (s, 6H), 3.82 (s, 3H).

Workup

  1. additionwas added over 15 min
  2. temperaturewhile maintaining an internal temperature below −50° C
  3. customquenched with a saturated NH4Cl solution
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate
  6. dry with materialThe combined organic phases were dried over anhydrous magnesium sulfate
  7. customthe solvent was removed under reduced pressure The resulting crude {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-1-hydroxy-prop-2-ynyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester
  8. dissolutionwas dissolved in dichloromethane (50 mL)
  9. waitaged at room temperature under nitrogen for 2.5 h
  10. filtrationThe reaction was then filtered through a pad of celite
  11. concentrationThe combined organic was concentrated under reduced pressure

Sources & evidence

ORD record
ord-d687e27392644fd7af5f936828ee1c68
Source dataset
uspto-grants-2007_04
Patent number
US07202247B2

Reaction notes

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