ChemicalBook CAS DataBase List Methyl 5-broMothiophene-3-carboxylate

Methyl 5-broMothiophene-3-carboxylate synthesis

6synthesis methods

Product Name:Methyl 5-broMothiophene-3-carboxylate
CAS Number:88770-19-8
Molecular formula:C6H5BrO2S
Molecular Weight:221.07

67-56-1 Synthesis

67-56-1
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100523-84-0
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88770-19-8
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$31.00/250mg

Yield: 91%

Reaction Conditions:

Stage #1:methanol;2-bromothiophene-4-carboxylic acid with sulfuric acid for 12 h;Reflux;
Stage #2: with sodium hydrogencarbonate in water

Steps:

59; 60
A solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) was added slowly to a stirred solution of Int-1 (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0° C. and stirred at room temperature for 20 minutes. The reaction mixture was then poured into ice water while stirring vigorously. The white precipitated solid was filtered, washed with water and recrystallised from hot water to afford pure Int-2 as white solid (3.68 g, 46%). ¹H NMR (200 MHz, dmso-d₆): δ 7.55 (s, 1H), 8.17 (s, 1H). To a stirred solution of Int-2 (3.4 g, 16.42 mmol) in methanol (40 mL) was added H₂SO₄(321 mg, 3.28 mmol) and stirred under reflux for 12 hours. Volatiles from the reaction mixture were distilled off under reduced pressure and the resulting residue was extracted with DCM (75 mL). The organic extract was washed with water (40 mL), saturated aqueous NaHCO₃solution (40 mL), brine (40 mL) and dried over Na₂SO₄, filtered and concentrated under vacuum to afford pure Int-3 as colorless viscous oil (3.3 g, 91%). ¹H NMR (200 MHz, dmso-d₆): δ 7.98 (s, 1H), 7.44 (s, 1H), 3.87 (s, 3H). To a stirred solution of Int-3 (0.5 g, 2.26 mmol) in dioxane (25 mL) was added Int-4 (0.51 g, 2.26 mmol) followed by Pd (OAc) 2 (105 mg, 0.45 mmol), xanthpos (265 mg, 0.497 mmol) and CS₂CO₃(1.18 g, 3.62 mmol). The reaction mixture was degassed under vacuum, bubbled with N₂for 10 minutes and stirred under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure and was purified by column chromatography to isolate product and a very close spot together eluting with EtOAc. This mixture (140 mg) was further purified with preparative HPLC to obtain pure Int-5 as a yellow solid (80 mg, 10%). Mass (m/z): 366.0 [M⁺+1]. ¹H NMR (200 MHz, dmso-d₆): 9.50 (d, J=7 Hz, 1H), 8.51 (d, J=7 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.74 (brs, 1H), 7.66 (d, J=11.8 Hz, 1H), 7.35 (d, J=7.4 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J=5.6 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.73 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.91 mmol) in THF: MeOH: H₂O (2:1:2) (50 ml) was added LiOH (0.24 g, 5.74 mmol) at room temperature and stirred while heating at 50° C. for 16 hours. Volatiles from the reaction mixture were distilled off under reduced pressure, the reaction mixture was acidified to about pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to afford pure Int-6 (0.51 g, 76%). Mass (m/z): 352.0 [M⁺+1]. ¹H NMR (200 MHz, dmso-d₆): δ 12.45 (brs, 1H), 10.87 (s, 1H), 9.70 ((brs, 1H), 8.60 (d, J=4.68 Hz, 1H), 7.67-7.59 (m, 2H), 7.45 (t, J=8.4 Hz, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.04 (s, 2H), 2.65 (s, 3H).