Hydrochloric Acid → Lithium diisopropylamide

HRID 275756Notes

Reaction equation

HRID 275756 reaction equation
C1N=CN(C(N2C=[N:11][CH:10]=[CH:9]2)=O)C=1.[C:13]([OH:21])(=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([Li:26])[CH2:23][CH2:24][CH3:25].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=1.[N-]1C=CN=C1.Cl>O1CCCC1>[CH:24]([N-:11][CH:10]([CH3:13])[CH3:9])([CH3:25])[CH3:23].[Li+:26].[CH3:39][O:38][C:36](=[O:37])[CH:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 5922Isonicotinic AcidHCID 682631,1'-CarbonyldiimidazoleHCID 90266Methyl 4-methoxyphenylacetateHCID 3386966ImidazolateHCID 178418339Butyllithium

Product 2

HCID 2724682Lithium diisopropylamideHCID 54318349HCID 54318349, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

N,N-Carbonyldiimidazole (20.3 g) was added portionwise to a stirred suspension of isonicotinic acid (15.4 g) in dry tetrahydrofuran (200 cm3). The gently effervescent mixture was stirred at room temperature for 90 minutes, forming an orange solution. A solution of lithium diisopropylamide was prepared by the addition of n-butyllithium (2.5 M, hexanes; 100 cm3) to a stirred solution of dilsopropylamine (35 cm3) in dry tetrahydrofuran (250 cm3) at 0° C. under nitrogen. The solution was cooled to −78° C. for 15 minutes, followed by the dropwise addition of a solution of methyl 2-(4-methoxyphenyl)acetate (45 g) in dry tetrahydrofuran (50 cm3) at −78° C. The yellow enolate solution was stirred at −78° C. for 20 minutes, followed by addition of the imidazolide solution dropwise via cannula. After stirring at −78° C. for 45 minutes the bright yellow suspension was warmed to room temperature. The mixture was poured into aqueous hydrochloric acid (1.3 M; 700 cm3) and washed with hexane (200 cm3). The aqueous solution was basified to pH 3 with aqueous sodium hydroxide (4 M) and then to pH 7 with saturated aqueous sodium hydrogencarbonate. The neutralised solution was extracted with dichloromethane (2×400 cm3). The organic extracts were washed with brine (300 cm3), dried (magnesium sulphate), filtered and concentrated to give a brown oil that crystallised on standing. The material was triturated with ethyl acetate-diethyl ether (1:1; 50 cm3) and filtered to give 2-(4-methoxyphenyl)-3-oxo-3-(pyridin-4-yl)propionic acid methyl ester as an off-white solid (14.7 g; 42%). δH (250 MHz; CDCl3) 3.77 (3 H, s, OCH3), 3.79 (3 H, s, OCH3), 5.48 (1 H, s, MeO2CCH), 6.90 (2 H, d, J 9, methoxyphenyl H-2), 7.28 (2 H, d, J 9, methoxyphenyl H-3), 7.70 (2 H, d, J 6, pyridyl H-3) and 8.77 (2 H, d, J 6, pyridyl H-2).

Workup

  1. customforming an orange solution
  2. temperatureThe solution was cooled to −78° C. for 15 minutes
  3. stirringAfter stirring at −78° C. for 45 minutes the bright yellow suspension
  4. temperaturewas warmed to room temperature
  5. washwashed with hexane (200 cm3)
  6. extractionThe neutralised solution was extracted with dichloromethane (2×400 cm3)
  7. washThe organic extracts were washed with brine (300 cm3)
  8. dry with materialdried (magnesium sulphate)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give a brown oil that
  12. customcrystallised
  13. customThe material was triturated with ethyl acetate-diethyl ether (1:1; 50 cm3)
  14. filtrationfiltered

Sources & evidence

ORD record
ord-98b91491d9bb43acaf97086edf4ea589
Source dataset
uspto-grants-2002_03
Patent number
US06352994B2

Reaction notes

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