methyl 5-hydroxy-1-benzofuran-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.4 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (550 mg, 1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile followed by addition of cesium carbonate (700 mg, 2.1 mmol). The reaction was then stirred at 60° C. for 2 hours, filtered and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes), gave the title compound (410 mg, 61%) as a pale yellow solid. M.p. 132-133° C.; IR (thin film) cm−1: 1731; 400 MHz 1H NMR (DMSO-d6) δ 7.95 (d, 2H, J=8.1 Hz), 7.79 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d, 1H, J=9.0 Hz), 4.44 (s, 2H), 3.82 (s, 3H); MS m/z 464 (M+1); Anal. Calc'd for C22H16F3N1O3S2 C, 57.01; H, 3.48; N, 3.02, found: C, 56.94; H, 3.44; N, 2.84. filtered concentrated in vacuo Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl ester (300 mg, 1.4 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (550 mg, 1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile followed by addition of cesium carbonate (700 mg, 2.1 mmol). The reaction was then stirred at 60° C. for 2 hours, filtered and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes), gave the title compound (410 mg, 61%) as a pale yellow solid. M.p. 132-133° C.; IR (thin film) cm−1: 1731; 400 MHz 1H NMR (DMSO-d6) δ 7.95 (d, 2H, J=8.1 Hz), 7.79 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d, 1H, J=9.0 Hz), 4.44 (s, 2H), 3.82 (s, 3H); MS m/z 464 (M+1); Anal. Calc'd for C22H16F3N1O3S2 C, 57.01; H, 3.48; N, 3.02, found: C, 56.94; H, 3.44; N, 2.84. filtered concentrated in vacuo Purification by flash column chromatography (gradient elution: 5% EtOAc/hexanes to 45% EtOAc/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-dimethylcarbamoylsulfanyl-benzofuran-2-carboxylic acid methyl ester (0.5 g, 1.8 mmol) and potassium hydroxide (0.5 g, 12.5 mmol) in 25 ml 2:1 ethanol/water was heated at reflux for 18 hours. The reaction was then cooled, acidified with 2 M HCl, extracted 2×25 mL EtOAc, dried (Na2SO4) and the solvent removed in vacuo to give 350 mg of the crude product. The crude mixture was then refluxed overnight in 25 mL MeOH and catalytic H2SO4. The reaction was then cooled, concentrated in vacuo, taken up in EtOAc and washed with brine. The organic layer was then dried (Na2SO4) and concentrated in vacuo to give 330 mg (95%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 7.66 (s, 1H), 7.62 (s, 1H), 7.57(d, 1H, J=9.0 Hz), 7.37 (d, 1H, J=9.0 Hz), 5.49 (s(br), 1H), 3.85 (s, 3H). Preparation of 5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-benzofuran-2-carboxylic acid methyl ester (Compound 6E) at reflux for 18 hours The reaction was then cooled extracted 2×25 mL EtOAc dried (Na2SO4) the solvent removed in vacuo to give 350 mg of the crude product The reaction was then cooled concentrated in vacuo washed with brine The organic layer was then dried (Na2SO4) concentrated in vacuo