N-Methoxy-N-methylbutyramide → tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate

HRID 1481733Notes

Reaction equation

HRID 1481733 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[CH:5]2.[Li]CCCC.CON(C)[C:32](=[O:36])[CH2:33][CH2:34][CH3:35]>C1COCC1>[C:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=[CH:5]2)(=[O:36])[CH2:33][CH2:34][CH3:35]

Participants

5

Reactant 3

HCID 13704543N-Methoxy-N-methylbutyramideHCID 71284358tert-butyl 3-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 71284618tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylateYield 70%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To solution of tert-butyl 3-(5-bromo-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (1.207 g, 3.18 mmol) in THF (13 mL) at −78° C. was added solution of n-BuLi (2.5M hexanes, 1.50 mL, 3.75 mmol) dropwise over 10 min. The reaction was stirred at −78° C. for 10 min, then a solution of N-methoxy-N-methylbutyramide (0.50 g, 3.81 mmol) in THF (2.0 mL) was added dropwise. The reaction was slowly allowed to warm to −50° C. before it was quenched with NH4Cl (aqueous saturated, 10 mL). Once ambient temperature was reached in the reaction mixture, the product was extracted with EtOAc (3×20 mL). Combined organics were washed with NaCl (aqueous saturated) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using EtOAc/hexanes (gradient 0-60%) to afford tert-butyl 3-(5-butyryl-1-methyl-1H-indol-2-yl)pyrrolidine-1-carboxylate (0.823 g) in 70% yield.

Workup

  1. temperatureto warm to −50° C. before it
  2. customwas quenched with NH4Cl (aqueous saturated, 10 mL)
  3. customOnce ambient temperature
  4. extractionthe product was extracted with EtOAc (3×20 mL)
  5. washCombined organics were washed with NaCl (aqueous saturated)
  6. dry with materialdried over Na2SO4
  7. customUpon solvent removal residue
  8. customwas purified by column chromatography

Sources & evidence

ORD record
ord-91e6d7cad4d3401ab3ed23c95b7a5ab2
Source dataset
uspto-grants-2016_08
Patent number
US09409905B2

Reaction notes

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