Diethyl Malonate → 2-Thieno[3,2-b]pyridin-7-yl-malonic Acid Diethyl Ester

HRID 910100Notes

Reaction equation

HRID 910100 reaction equation
[H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12>O1CCOCC1.[Cu]Br>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[CH:22][S:23][C:16]=12)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]

Participants

6

Reactant 3

HCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 667211077-Bromothieno[3,2-b]pyridine

Product 1

HCID 673377292-Thieno[3,2-b]pyridin-7-yl-malonic Acid Diethyl EsterYield 57%

Reagents, catalysts & solvents 2

HCID 24593copper(I) bromideCatalystHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Charge a flask containing sodium hydride (17.45 g, 0.44 moles) with anhydrous dioxane (500 ml) while cooling at 0° C. Add diethyl malonate (69.88 g, 0.44 moles) dropwise over one hour. Upon reaching ambient temperature, add copper (I) bromide (62.59 g, 0.44 moles). Add 7-bromothieno[3,2-b]pyridine (18.68 g, 87.26 mmol) as a solution in dioxane (50 mL). Heat the reaction to reflux for 18 hours. Concentrate the reaction solution to ˜175 mL. Pour the concentrate into concentrated ammonium hydroxide (2.5 L). Extract the aqueous phase with ethyl acetate (6×300 mL). Wash the organic layers exhaustively with 2 N sodium hydroxide until the blue color dissipates. Treat the organic layers with magnesium sulfate, filter and concentrate. Purification on silica utilizing a solution of 1:1:3 of ether, ethyl acetate and hexane as eluent yields the desired compound (14.6 gm, 57%).

Workup

  1. additionCharge a flask
  2. customUpon reaching ambient temperature
  3. temperatureHeat
  4. customthe reaction
  5. temperatureto reflux for 18 hours
  6. concentrationConcentrate the reaction solution to ˜175 mL
  7. additionPour the
  8. concentrationconcentrate into concentrated ammonium hydroxide (2.5 L)
  9. extractionExtract the aqueous phase with ethyl acetate (6×300 mL)
  10. washWash the organic layers exhaustively with 2 N sodium hydroxide until the blue color dissipates
  11. additionTreat the organic layers with magnesium sulfate
  12. filtrationfilter
  13. concentrationconcentrate
  14. customPurification on silica utilizing a solution of 1:1:3 of ether, ethyl acetate and hexane as eluent

Sources & evidence

ORD record
ord-f0e69fd2528641fc9b1349ed66cd0c5d
Source dataset
uspto-grants-2011_09
Patent number
US08022065B2

Reaction notes

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