ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate [see step 2 ACI-02] (8 g, 32.0 mmol) in DMSO (30 mL) was added NaOH (2.56 g, 64.1 mmol) and the reaction mixture was stirred at 70° C. for 20 h. An additional portion of NaOH (0.5 g, 12.5 mmol) was added and stirring at 70° C. was continued for 30 min. The reaction mixture was cooled in an ice bath and acidified with aqueous 1M KHSO4 (80 mL). The solid was filtered off and washed with aqueous 1M KHSO4 (20 mL), H2O (3×25 mL) and heptane (3×25 mL) and dried on air. The residue was dissolved in EtOAc (600 mL), dried (Na2SO4) and the solvent was removed in vacuo. The product was stirred in i-Pr2O/heptane (1:1, 100 mL). The solid was filtered and off dried in vacuo to give the desired product as a a white solid (6.04 g, 85%). stirring at 70° C. was continued for 30 min The reaction mixture was cooled in an ice bath The solid was filtered off washed with aqueous 1M KHSO4 (20 mL), H2O (3×25 mL) and heptane (3×25 mL) dried on air The residue was dissolved in EtOAc (600 mL) dried (Na2SO4) the solvent was removed in vacuo The product was stirred in i-Pr2O/heptane (1:1, 100 mL) The solid was filtered off dried in vacuo

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

Procedure: This reaction was carried out in 5 batches using the same procedure. To a mixture of ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate [for synthesis see ACI-01] (1.25 g, 5.01 mmol), K2HPO4 (2.62 g, 15 mmol) and dichlortris(1,10-phenanthroline)-ruthenium(II) hydrate (71 mg, 0.10 mmol) in argon degassed dry MeCN (35 mL) was added CF3SO2Cl (1.60 mL, 15 mmol). The reaction mixture was stirred for 16 h at room temperature adjacent to a fluorescent light bulb (E27-32W, 4000K, 65 mA). After 16 h, an additional amount of CF3SO2Cl (0.20 mL, 1.88 mmol) was added and the reaction mixture was stirred overnight at room temperature adjacent to a fluorescent light bulb. All reaction mixtures were combined and diluted with EtOAc (150 mL) and H2O was added. The aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined and the solvent was evaporated to give an oil. The crude product was purified by flash chromatography (silica, gradient heptane/EtOAc, 1:0→1:1) to furnish the desired product (4.59 g, 58%). degassed dry MeCN (35 mL) All reaction mixtures was added The aqueous layer was extracted with EtOAc (150 mL) the solvent was evaporated to give an oil The crude product was purified by flash chromatography (silica, gradient heptane/EtOAc, 1:0→1:1)

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

Procedure: Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step. at 0° C the solvents were evaporated under reduced pressure The residue was partitioned between EtOAc (400 mL) and H2O (400 mL) The organic phase was washed with (100 mL) dried over Na2SO4 filtered evaporated to dryness under reduced pressure

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

Procedure: Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step. at 0° C the solvents were evaporated under reduced pressure The residue was partitioned between EtOAc (400 mL) and H2O (400 mL) The organic phase was washed with (100 mL) dried over Na2SO4 filtered evaporated to dryness under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate [see step 2 ACI-02] (8 g, 32.0 mmol) in DMSO (30 mL) was added NaOH (2.56 g, 64.1 mmol) and the reaction mixture was stirred at 70° C. for 20 h. An additional portion of NaOH (0.5 g, 12.5 mmol) was added and stirring at 70° C. was continued for 30 min. The reaction mixture was cooled in an ice bath and acidified with aqueous 1M KHSO4 (80 mL). The solid was filtered off and washed with aqueous 1M KHSO4 (20 mL), H2O (3×25 mL) and heptane (3×25 mL) and dried on air. The residue was dissolved in EtOAc (600 mL), dried (Na2SO4) and the solvent was removed in vacuo. The product was stirred in i-Pr2O/heptane (1:1, 100 mL). The solid was filtered and off dried in vacuo to give the desired product as a a white solid (6.04 g, 85%). stirring at 70° C. was continued for 30 min The reaction mixture was cooled in an ice bath The solid was filtered off washed with aqueous 1M KHSO4 (20 mL), H2O (3×25 mL) and heptane (3×25 mL) dried on air The residue was dissolved in EtOAc (600 mL) dried (Na2SO4) the solvent was removed in vacuo The product was stirred in i-Pr2O/heptane (1:1, 100 mL) The solid was filtered off dried in vacuo

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

Procedure: This reaction was carried out in 5 batches using the same procedure. To a mixture of ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate [for synthesis see ACI-01] (1.25 g, 5.01 mmol), K2HPO4 (2.62 g, 15 mmol) and dichlortris(1,10-phenanthroline)-ruthenium(II) hydrate (71 mg, 0.10 mmol) in argon degassed dry MeCN (35 mL) was added CF3SO2Cl (1.60 mL, 15 mmol). The reaction mixture was stirred for 16 h at room temperature adjacent to a fluorescent light bulb (E27-32W, 4000K, 65 mA). After 16 h, an additional amount of CF3SO2Cl (0.20 mL, 1.88 mmol) was added and the reaction mixture was stirred overnight at room temperature adjacent to a fluorescent light bulb. All reaction mixtures were combined and diluted with EtOAc (150 mL) and H2O was added. The aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined and the solvent was evaporated to give an oil. The crude product was purified by flash chromatography (silica, gradient heptane/EtOAc, 1:0→1:1) to furnish the desired product (4.59 g, 58%). degassed dry MeCN (35 mL) All reaction mixtures was added The aqueous layer was extracted with EtOAc (150 mL) the solvent was evaporated to give an oil The crude product was purified by flash chromatography (silica, gradient heptane/EtOAc, 1:0→1:1)

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

Procedure: Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step. at 0° C the solvents were evaporated under reduced pressure The residue was partitioned between EtOAc (400 mL) and H2O (400 mL) The organic phase was washed with (100 mL) dried over Na2SO4 filtered evaporated to dryness under reduced pressure