Diisopropylamine → 4-Tert-butyl 1-methyl 2-(4-chlorophenyl)succinate

HRID 82407Notes

Reaction equation

HRID 82407 reaction equation
[Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1

Participants

7

Reactant 5

HCID 7912DiisopropylamineHCID 79177tert-Butyl bromoacetateHCID 104196Methyl 4-chlorophenylacetateHCID 2724682Lithium diisopropylamideHCID 178418339Butyllithium

Product 1

HCID 666183864-Tert-butyl 1-methyl 2-(4-chlorophenyl)succinateYield 88.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

n-BuLi (1.60M in hexanes, 35.6 mL, 56.9 mmol) was added to a 0° C. solution of diisopropylamine (8.35 mL, 59.6 mmol) in THF (200 mL). The mixture was stirred at 0° C. for 30 minutes and then cooled to −78° C. A solution of methyl 2-(4-chlorophenyl)acetate (10.0 g, 54.2 mmol) in THF (10 mL) was added to the −78° C. LDA solution by syringe, which was then stirred for 45 minutes. Neat tert-butyl bromoacetate (9.60 mL, 65.0 mmol) was added by syringe, and the reaction was stirred for 15 minutes at −78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH4Cl solution, and the solvent(s) were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic portion was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified on silica gel (95:5 hexanes:EtOAc) to afford the 4-tert-butyl 1-methyl 2-(4-chlorophenyl)succinate as a pale yellow oil (14.3 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=7.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 2H), 4.00 (dd, J=9.6, 5.6 Hz, 1H), 3.67 (s, 3H), 3.07 (dd, J=16.4, 9.6 Hz, 1H), 2.58 (dd, J=16.8, 6.0 Hz, 1H), 1.40 (m, 3H).

Workup

  1. temperaturecooled to −78° C
  2. stirringthe reaction was stirred for 15 minutes at −78° C
  3. customThe bath was removed
  4. temperatureto warm to room temperature
  5. stirringAfter stirring an additional 5 hours
  6. customthe reaction mixture was quenched with saturated NH4Cl solution
  7. customthe solvent(s) were removed in vacuo
  8. extractionThe oily mixture was extracted with ethyl acetate
  9. dry with materialThe organic portion was dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude oil was purified on silica gel (95:5 hexanes:EtOAc)

Sources & evidence

ORD record
ord-896f23fac31341eaa51c3d9c46aca015
Source dataset
uspto-grants-2014_09
Patent number
US08846681B2

Reaction notes

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