Ethylene Glycol → 5-[1,3]Dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid

HRID 1685694Notes

Reaction equation

HRID 1685694 reaction equation
[CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.CC(=O)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:12][CH2:13][O:14][CH:1]1[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11]

Participants

6

Reactant 2

HCID 174Ethylene GlycolHCID 532126825-Formyl-4-methylthiophene-2-carboxylic acid

Product 1

HCID 672655315-[1,3]Dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acidYield 97.9%

Reagents, catalysts & solvents 3

HCID 521998p-Toluenesulfonic acid monohydrateCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A suspension of 5-formyl-4-methyl-thiophene-2-carboxylic acid (3.00 g, 17.6 mmol), ethylene glycol (3.28 g, 52.9 mmol) and p-toluene sulfonic acid hydrate (61 mg, 0.353 mmol) in toluene (80 mL) is refluxed for 3 h in a Dean-Stark apparatus. The clear solution is diluted with EA and washed twice with water. The washings are extracted back with EA. The combined organic extracts are dried over Na2SO4, filtered, concentrated and dried to give 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid (3.69 g) as a pale yellow resin, LC-MS: tR=0.46 min, [M+1]+=215.15. b) To a mixture of 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid (3.00 g, 14.0 mmol), HOBt (2.52 g, 16.8 mmol) and EDC (2.95 g, 15.4 mmol) in isopropanol (240 mL), hydrazine hydrate (1.50 g, 29.4 mmol) is added at 0° C. The suspension is stirred at 0° C., diluted with DMF and warmed to rt. Stirring is continued at rt for 2 h before the solvent is evaporated. The residue is dissolved in acetonitrile and separated by prep. HPLC (XBridge C18, 50×50 +100×50 mm, 10 μm, gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give the title compound (2.43 g) as a colourless solid; LC-MS: tR=0.57 min, [M+1]+=228.96; 1H NMR (D6-DMSO): δ2.20 (s, 3H), 3.90-3.99 (m, 2H), 3.99-4.08 (m, 2H), 4.43 (s, 2H), 6.06 (s, 1H), 7.43 (s, 1H), 9.69 (s, 1H).

Workup

  1. temperatureis refluxed for 3 h in a Dean-Stark apparatus
  2. washwashed twice with water
  3. extractionThe washings are extracted back with EA
  4. dry with materialThe combined organic extracts are dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customdried

Sources & evidence

ORD record
ord-f9a64cf85c6b4ec3a58da7f820a9331d
Source dataset
uspto-grants-2012_04
Patent number
US08148410B2

Reaction notes

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