ChemicalBook CAS DataBase List 5-(4-Chlorophenyl)thiophene-2-carboxylic acid

5-(4-Chlorophenyl)thiophene-2-carboxylic acid synthesis

12synthesis methods

Product Name:5-(4-Chlorophenyl)thiophene-2-carboxylic acid
CAS Number:40133-14-0
Molecular formula:C11H7ClO2S
Molecular Weight:238.69

ethyl 5-(4-chlorophenyl)-2-thiophenecarboxylate

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5-(4-Chlorophenyl)thiophene-2-carboxylic acid

40133-14-0
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Yield:40133-14-0 96%

Reaction Conditions:

Stage #1: ethyl 5-(4-chlorophenyl) thiophene-2-carboxylatewith sodium hydroxide;water in methanol; for 6 h;Heating / reflux;
Stage #2: with hydrogenchloride in methanol;water at 20; pH=3;

Steps:

9.B

A mixture of ethyl 5-bromothiophene-2-carboxylate (1.0 g, 4.25 mmol), 4-chlorophenylboronic acid (0.998 g, 6.38 mmol), 2.0 M aq NaHCO₃(6.38 ml, 12.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.492 g, 0.425 mmol) in DMF (40 ml) under nitrogen was stirred at 100° C. under nitrogen in a sealed tube for 18 hours as described in WO 2007/011284. The reaction was then cooled to RT, diluted with saturated aq NaHCO₃(40 ml) and extracted with EtOAc (40 ml). The EtOAc extracts were dried over Na₂SO₄and concentrated. The crude product was purified by ISCO chromatography on a silica gel column (120 g) employing a 10 min gradient ranging from hexane to 30% EtOAc to elute ethyl 5-(4-chlorophenyl)thiophene-2-carboxylate (1.05 g, 3.94 mmol, 93% yield) as a white solid. LC MS at t=2.70 min. (m+H=267) Phenomenex S5 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.39 (t, J=7.18 Hz, 3H), 4.37 (q, J=7.22 Hz, 2H), 7.43-7.51 (m, 3H), 7.71 (d, J=8.56 Hz, 2H), 7.78 (d, J=4.03 Hz, 1H).A mixture of ethyl 5-(4-chlorophenyl)thiophene-2-carboxylate (1.05 g, 3.94 mmol), methanol (40 ml) and 1.0 M aq NaOH (15.75 ml, 15.75 mmol) was stirred at reflux for 6 hours. Upon cooling to RT, the reaction was acidified to pH 3 with conc. HCl and extracted with EtOAc (60 ml). The EtOAc layer was dried over Na₂SO₄and concentrated to yield 5-(4-chlorophenyl)thiophene-2-carboxylic acid (902 mg, 3.78 mmol, 96% yield) as an off-white solid. LC MS at t=2.44 min. (m+H=240) Phenomenex S5 C18 4.6×30 mm column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient over 2 min at 5 mL/min with 1 min hold at the end of the gradient. ¹H NMR (400 MHz, DMSO) δ ppm 7.36-7.97 (m, 6H), 13.19 (s, 1H).

References:

US2008/269110,2008,A1 Location in patent:Page/Page column 18

7311-63-9 Synthesis