Sodium Carbonate → Methyl 5-phenylthiophene-2-carboxylate

Participants

Reaction Steps

Thionyl chloride (350 mg, 3.0 mmol) was added to cold (0° C.) solution of 5-bromo-thiophene-2-carboxylic acid (100 mg, 0.4 mmol) in MeOH (2 mL) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure The residue was diluted with ethylacetate. The organic layer was washed with water followed by saturated brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 200 mg of 5-bromo-thiophene-2-carboxylic acid methyl ester. Aqueous 2M Na2CO3 solution (7.35 mL) was added to a stirred solution of 5-bromo-thiophene-2-carboxylic acid methyl ester (1.0 g, 4.5 mmol) and phenylboronic acid (660 mg, 5.4 mmol) in DME (15 mL) purged with N2 for 10 minutes. Pd (PPh3)4 (250 mg, 0.22 mmol) was added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated. Purification by column chromatography (using silica gel 60-120 and 2% EtOAc in hexane as eluent) afforded 900 mg (92% Yield) of 5-phenyl-thiophene-2-carboxylic acid methyl ester. A solution of 5-phenyl-thiophene-2-carboxylic acid methyl ester (800 mg, 3.9 mmol) in THF (3 mL) was added dropwise to reaction flask containing LAH (299 mg, 7.9 mmol) at 0° C. and stirring was continued at ambient temperature for 3 hrs. The reaction mixture was quenched with aqueous NaOH solution and filtered through celite. The filtrated was collected was extracted with ethyl acetate, dried over sodium sulfate and concentrated to afford 710 mg (91.1% Yield) of (5-phenyl-thiophen-2-yl)-methanol IBX (3.0 g, 11.0 mmol) was added to a stirred solution of (5-phenyl-thiophen-2-yl)-methanol (700 mg, 3.6 mmol) in THF (10 mL) and stirring was continued at ambient temperature overnight. The reaction mixture was filtered through celite, filtrated was collected, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated. Purification by column chromatography (using silica gel 60-120 and 5% EtOAc in hexane as eluent) afforded 600 mg (89.5% Yield) of 5-phenyl-thiophene-2-carbaldehyde. 5-phenyl-thiophene-2-carbaldehyde (500 mg, 2.6 mmol) and azido-acetic acid ethyl ester (1.3 g, 10.4 mmol) were added to a stirred solution of sodium metal (240 mg, 10.4 mmol) dissolved in EtOH (10 mL) and cooled to 0° C. while stirring under N2 atmosphere. Stirring was continued at 11° C. for 1.5 hrs. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulfate and concentrated to afford 500 mg (crude) of 2-azido-3-(5-phenyl-thiophen-2-yl)-acrylic acid ethyl ester. A mixture of 2-azido-3-(5-phenyl-thiophen-2-yl)-acrylic acid ethyl ester (350 mg, crude) in xylene (5 mL) was stirred at reflux temperature for 30 minutes. The reaction mixture was concentrated. Purification by column chromatography (using silica gel 60-120 and 15% EtOAc in hexane as eluent) afforded 75 mg of 2-phenyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester. LiOH.H2O (17 mg, 0.4 mmol) was added to a stirred solution of 2-phenyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (55 mg, 0.2 mmol) in a mixture of methanol (0.5 mL), THF (11 mL) and H2O (1 mL). The reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated. The residue was diluted with water, acidified with conc. HCl, and extracted with ethyl acetate. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure to afford 42 mg (87.5%) of 2-phenyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid.

Provenance & Evidence