Acetic Acid → 5-Diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid

HRID 1685696Notes

Reaction equation

HRID 1685696 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.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([N:14]([CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])[CH2:15][CH3:16])[CH3:13]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8021DiethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 532126825-Formyl-4-methylthiophene-2-carboxylic acid

Product 1

HCID 672654805-Diethylaminomethyl-4-methyl-thiophene-2-carboxylic acidYield 53.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-formyl-4-methyl-thiophene-2-carboxylic acid (6.90 g, 40.5 mmol) in THF (150 mL), diethylamine (5.93 g, 81.1 mmol) and acetic acid (10 mL) followed by sodium triacetoxyborohydride (14.32 g, 60.8 mmol) is added. The mixture becomes slightly warm. The reaction mixture is stirred at rt for 16 h before it is concentrated and separated by CC on silica gel eluting with EA containing 0-50% of methanol to give the title compound (4.95 g) containing large amount of diethylammonium salts. The material (4.94 g, 21.8 mmol) is therefore dissolved in methanol (70 mL) and treated with chloro trimethylsilane (23.7 g, 218 mmol). The mixture is stirred at 50° C. for 18 h before it is concentrated, dissolved in EA and washed with sat. aq. NaHCO3 solution. The organic extract is dried over Na2SO4, filtered, concentrated and dried to give 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid methyl ester (4.05 g) as a yellow oil; 1H NMR (CDCl3): δ 1.08 (t, J=7.0 Hz, 6H), 2.19 (s, 3H), 2.59 (q, J=7.0 Hz, 4H), 3.67 (s, 2H), 3.87 (s, 3H), 7.28 (s, 1H), 7.52 (s, 1H). This material is dissolved in 1 N aq. HCl (80 mL) and stirred at 65° C. for 214 h. The solvent is evaporated and the residue is dried under high vacuum to give the title compound (3.56 g) as a pale beige solid; LC-MS: tR=0.26 min; [M+1]+=228.20; 1H NMR (D6-DMSO): δ 1.28 (t, J=7.3 Hz, 6H), 2.31 (s, 3H), 3.12 (q, J=6.8 Hz, 4H), 4.48 (s, 2H), 7.59 (s, 1H).

Workup

  1. additionis added
  2. temperatureThe mixture becomes slightly warm
  3. concentrationis concentrated
  4. customseparated by CC on silica gel eluting with EA containing 0-50% of methanol

Sources & evidence

ORD record
ord-fb0bfbf3f6e441c59042fdfcaf73dcb4
Source dataset
uspto-grants-2012_04
Patent number
US08148410B2

Reaction notes

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