Methyl 5-broMothiophene-3-carboxylate Chemical Properties

Melting point:

43-44 °C

Boiling point:

244.6±20.0 °C(Predicted)

Density 

1.662±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2–8 °C

Appearance

Off-white to light brown Solid

Safety Information

HS Code 

2934999090

Methyl 5-broMothiophene-3-carboxylate Usage And Synthesis

Synthesis

1. Add a solution of bromine (2 mL, 39.06 mmol) in glacial acetic acid (64 mL) slowly dropwise to a stirred solution of 5-bromothiophene-3-carboxylic acid (5 g, 39.06 mmol) in glacial acetic acid (37 mL) at 0 °C. Stirring was done for 20 minutes at room temperature. The reaction mixture was poured into ice water with vigorous stirring. The white solid precipitate was collected by filtration, washed with water and recrystallized from hot water to give pure 5-bromothiophene-3-carboxylic acid bromide (Int-2) as a white solid (3.68 g, 46%).1H NMR (200 MHz, DMSO-d6): δ 7.55 (s, 1H), 8.17 (s, 1H). 2. Int-2 (3.4 g, 16.42 mmol) was dissolved in methanol (40 mL), H2SO4 (321 mg, 3.28 mmol) was added, and stirred at reflux for 12 hours. Volatiles were removed by distillation under reduced pressure and the residue was extracted with DCM (75 mL). The organic phase was washed sequentially with water (40 mL), saturated aqueous NaHCO3 (40 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give pure methyl 5-bromothiophene-3-carboxylate (Int-3) as a 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). 3. Int-3 (0.5 g, 2.26 mmol) was dissolved in dioxane (25 mL), and Int-4 (0.51 g, 2.26 mmol), Pd(OAc)2 (105 mg, 0.45 mmol), xanthic acid (265 mg, 0.497 mmol) and Cs2CO3 (1.18 g, 3.62 mmol) were added. After vacuum degassing, the reaction was stirred at reflux for 20 h under N2 protection. The reaction mixture was concentrated under reduced pressure and purified by column chromatography with the product eluting with EtOAc. The mixture was further purified by preparative HPLC (140 mg) to give pure Int-5 as a yellow solid (80 mg, 10%). Mass spectrum (m/z): 366.0 [M++1]. 1H NMR (200 MHz, DMSO-d6): δ 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). 4. Int-5 (0.7 g, 1.91 mmol) was dissolved in THF:MeOH:H2O (2:1:2, 50 mL), LiOH (0.24 g, 5.74 mmol) was added, and heated and stirred at 50 °C for 16 hours. Volatiles were removed by distillation under reduced pressure and the reaction mixture was acidified to pH 5-6 with 2N HCl. The precipitated solid was filtered and dried under vacuum to give pure Int-6 (0.51 g, 76%). Mass spectrum (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).

References

[1] Patent: US2010/29638, 2010, A1. Location in patent: Page/Page column 110
[2] Tetrahedron Letters, 2013, vol. 54, # 11, p. 1460 - 1462
[3] Journal of Materials Chemistry C, 2018, vol. 6, # 14, p. 3731 - 3742
[4] Patent: WO2005/9941, 2005, A1. Location in patent: Page 43-44
[5] Patent: WO2011/33255, 2011, A1. Location in patent: Page/Page column 72

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