methyl 4H-furo[3,2-b]pyrrole-5-carboxylate

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

Procedure: Using general procedure B, methyl 4H-furo[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 4-naphthalen-1-ylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 290.3 ([M−H]−).

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

Procedure: To a mixture of sodium hydride (0.29 g, 55% dispersion in paraffin liquid) and DMF (10 mL) was added methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (0.5 g) under ice-cooling, followed by stirring for 10 minutes and further 1-(bromomethyl)-4-chlorobenzene (0.81 g) was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1-3/1) to obtain 4-(4-chlorobenzyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.35 g). cooling by stirring at room temperature for 4 hours followed by extraction with ethyl acetate The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 5/1-3/1)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (5.00 g, 30.3 mmol) and KOH (3.40 g, 60.6 mmol) in DMF (100 mL) was cooled to −10° C. Iodine (7.31 g, 28.8 mmol) in DMF (40 mL) was charged via an addition funnel over 30 min. The resulting mixture was warmed to rt and stirred for additional 12 h. The reaction mixture was poured into water, adjusted with HCl (2 N) to pH 6-7, and extracted with EtOAc. The crude product was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) to give a light tan solid methyl 6-iodo-4H-furo[3,2-b]pyrrole-5-carboxylate (3.85 g, 44% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.98 (br, s, 1H); 7.55 (d, J=2 Hz, 1H); 6.52 (d, J=2 Hz, 1H); 3.91 (s, 3H). MS (m/z 291). The resulting mixture was warmed to rt extracted with EtOAc The crude product was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in hexanes)

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

Procedure: To a solution of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (1.0 g, 6.06 mmol) in CH2Cl2 (10 ml) was added triethyl amine (1.85 g, 18.2 mmol) and DMAP (148 mg 1.22 mol). Then BOC2O (2.0 g, 9.1 mmol) was added. The resulting mixture was stirred overnight. After the reaction was complete as judged TLC analysis (10% EtOAc/hexane), the reaction mixture was washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the crude product was purified by silica gel chromatography (20% EtOAc in hexane) to give 4-tert-butoxycarbonyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester as a white solid (987 mg, 62%). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.45 (d, J=1.47 Hz, 1H), 6.82 (s, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 1.55 (s, 9H). the reaction mixture was washed with water and brine dried over Na2SO4 After filtration the filtrate was concentrated the crude product was purified by silica gel chromatography (20% EtOAc in hexane)

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

Procedure: To a cold solution (ice-water bath) of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (1.0 g, 6.05 mmol) in DCM (10 mL) was added TBAF (1.0 M in THF, 9.0 mL, 9.0 mmol) and NBS (1.5 g, 7.9 mmol). The resulting dark colored solution was stirred from 0° C. to rt overnight. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed with water (100 mL) and brine (100 mL) and dried (Na2SO4). After filtration, the filtrate was concentrated by evaporation and the crude product was purified by silica gel chromatography (0-5% EtOAc/hexane) to afford a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.84 (broad, 1H, NH), 7.54 (d, J=2.2 Hz, 1H), 6.48 (d, J=1.83 Hz, 1H), 3.92 (s, 3H) ppm; m+/z 244 (100%), 246 (100%). washed with water (100 mL) and brine (100 mL) dried (Na2SO4) After filtration the filtrate was concentrated by evaporation the crude product was purified by silica gel chromatography (0-5% EtOAc/hexane) to afford a white solid

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

Procedure: Using general procedure B, methyl 4H-furo[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 4-naphthalen-1-ylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 290.3 ([M−H]−).