Ethyl Thioglycolate → 4-Isobutyl-5-methylthiophene-2-carboxylic acid

HRID 1676103Notes

Reaction equation

HRID 1676103 reaction equation
[Na].C([O:4][C:5](=[O:8])[CH2:6][SH:7])C.Cl[C:10]([CH3:18])=[C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:12]=O>C(O)C.C1COCC1.C(OCC)C>[CH2:14]([C:11]1[CH:12]=[C:6]([C:5]([OH:4])=[O:8])[S:7][C:10]=1[CH3:18])[CH:15]([CH3:17])[CH3:16]

Participants

7

Reactant 3

HCID 12185Ethyl ThioglycolateHCID 5360545SodiumHCID 866457643-Chloro-2-isobutyl-but-2-enal

Product 1

HCID 594978744-Isobutyl-5-methylthiophene-2-carboxylic acidYield 28.3%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

Sodium (10.7 g, 467 mmol) is dissolved in ethanol (500 mL) and the resulting solution is diluted with THF (100 mL) before mercapto-acetic acid ethyl ester (33.7 g, 280 mmol) dissolved in THF (70 mL) is slowly added at 5° C. The mixture is stirred at rt for 1 h before a solution of 3-chloro-2-isobutyl-but-2-enal (30 g, 187 mmol) in THF (100 mL) is slowly added at 8° C. The resulting yellow suspension is stirred at rt for 16 h. The reaction mixture is diluted with diethyl ether (500 mL) and is washed with dilute aq. NaOCl solution, followed by aq. 1N HCl and water. The organic extract is dried over MgSO4, filtered and evaporated. The remaining orange oil is dissolved in ethanol (150 mL) and 2N aq. LiOH (50 mL) is added. The mixture is stirred for 16 h at 50° C., acidified with 2 N aq. HCl and extracted with EA. The organic extract is dried over MgSO4, filtered and evaporated. The crude product is recrystallized from EA/heptane to give 4-isobutyl-5-methyl-thiophene-2-carboxylic acid (10.5 g) as colourless crystals; LC-MS: tR=0.92 min, [M+1+CH3CN]=240.16; 1H NMR (CDCl3): δ 7.59 (s, 1H), 2.40-2.37 (m, 5H), 1.84 (hept, J=7.0 Hz, 1H), 0.90 (d, J=7.0 Hz, 6H).

Workup

  1. additionis slowly added at 5° C
  2. additionis slowly added at 8° C
  3. washis washed with dilute aq. NaOCl solution
  4. extractionThe organic extract
  5. dry with materialis dried over MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. dissolutionThe remaining orange oil is dissolved in ethanol (150 mL)
  9. addition2N aq. LiOH (50 mL) is added
  10. stirringThe mixture is stirred for 16 h at 50° C.
  11. extractionextracted with EA
  12. extractionThe organic extract
  13. dry with materialis dried over MgSO4
  14. filtrationfiltered
  15. customevaporated
  16. customThe crude product is recrystallized from EA/heptane

Sources & evidence

ORD record
ord-af2858f123fe404592f154d635eff4f5
Source dataset
uspto-grants-2011_08
Patent number
US08003800B2

Reaction notes

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